VCV000002482.92 - ClinVar

NM_024577.4(SH3TC2):c.2860C>T (p.Arg954Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(40)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024577.4(SH3TC2):c.2860C>T (p.Arg954Ter)

Variation ID: 2482 Accession: VCV000002482.92

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q32 5: 149026872 (GRCh38) [ NCBI UCSC ] 5: 148406435 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Dec 28, 2024	Sep 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024577.4:c.2860C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078853.2:p.Arg954Ter	nonsense
NC_000005.10:g.149026872G>A
NC_000005.9:g.148406435G>A
NG_007947.2:g.41303C>T
LRG_269:g.41303C>T
LRG_269t1:c.2860C>T	LRG_269p1:p.Arg954Ter

... more HGVS ... less HGVS

Protein change

R954*

Other names

Canonical SPDI

NC_000005.10:149026871:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00060

The Genome Aggregation Database (gnomAD) 0.00067

The Genome Aggregation Database (gnomAD), exomes 0.00075

Exome Aggregation Consortium (ExAC) 0.00088

Links

ClinGen: CA115573 OMIM: 608206.0005 dbSNP: rs80338933 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SH3TC2		-	-	GRCh38 GRCh37	1752	1794

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Charcot-Marie-Tooth disease type 4C	Pathogenic/Likely pathogenic (14)	criteria provided, multiple submitters, no conflicts	Oct 25, 2023	RCV000002586.40
Susceptibility to mononeuropathy of the median nerve, mild	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 5, 2022	RCV000002587.16
Charcot-Marie-Tooth disease	Pathogenic (2)	criteria provided, single submitter	-	RCV000144877.12
not provided	Pathogenic/Likely pathogenic (15)	criteria provided, multiple submitters, no conflicts	Sep 1, 2024	RCV000255213.61
SH3TC2-related disorder	Pathogenic (2)	criteria provided, single submitter	Mar 20, 2018	RCV000282937.16
Charcot-Marie-Tooth disease type 4	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2024	RCV000168436.23
Charcot-Marie-Tooth disease type 4C Susceptibility to mononeuropathy of the median nerve, mild	Pathogenic (1)	criteria provided, single submitter	Apr 8, 2022	RCV000515338.12
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 23, 2023	RCV000622836.12
Tip-toe gait	no classifications from unflagged records (1)	no classifications from unflagged records	Sep 4, 2024	RCV001851586.11

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 19, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339051.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 14574644‚ 21840889‚ 25025039 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SH3TC2 Number of individuals with the variant: 3 Zygosity: Single Heterozygote Sex: mixed
Likely pathogenic (Oct 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: yes Allele origin: maternal	NeuroMeGen, Hospital Clinico Santiago de Compostela Accession: SCV000882617.1 First in ClinVar: Feb 04, 2019 Last updated: Feb 04, 2019	Zygosity: Single Heterozygote
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001335894.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447202.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Acute demyelinating polyneuropathy (present) , Polyneuropathy (present) Sex: male
Pathogenic (Jun 11, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064388.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the SH3TC2 gene demonstrated a sequence change, c.2860C>T, which results in the creation of a premature stop codon at amino acid … (more) DNA sequence analysis of the SH3TC2 gene demonstrated a sequence change, c.2860C>T, which results in the creation of a premature stop codon at amino acid position 954, p.Arg954*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SH3TC2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple patients with SH3TC2-related Charcot-Marie-Tooth disease type 4C (Senderek et al., 2003; Houlden et al., 2009.). (less)
Pathogenic (Jul 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581155.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM3_STR, PS4_MOD, PP1	Number of individuals with the variant: 1 Sex: female
Pathogenic (Nov 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021249.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198229.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Apr 15, 2014)	criteria provided, single submitter (Lee et al. (JAMA. 2014)) Method: clinical testing	Charcot-Marie-Tooth disease, type 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	UCLA Clinical Genomics Center, UCLA Study: CES Accession: SCV000255465.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 19, 2015	Age: 10-19 years Sex: female Testing laboratory: UCLA Clinical Genomics Center
Pathogenic (Mar 20, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	SH3TC2-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000454536.3 First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019	Publications: PubMed (9) PubMed: 25737037‚ 19272779‚ 20220177‚ 21840889‚ 25025039‚ 14574644‚ 16924012‚ 19744956‚ 18511281 Comment: The SH3TC2 c.2860C>T (p.Arg954Ter) variant is a stop-gained variant and is predicted to result in premature termination of the protein. The p.Arg954Ter variant is reported … (more) The SH3TC2 c.2860C>T (p.Arg954Ter) variant is a stop-gained variant and is predicted to result in premature termination of the protein. The p.Arg954Ter variant is reported in at least nine studies associated with Charcot-Marie-Tooth, type 4, and found in a total of 39 unrelated patients including 26 homozygotes and 13 compound heterozygote (Senderek et al. 2003; Azzedine et al. 2006; Lupo et al. 2009; Gosselin et al. 2008; Houlden et al. 2009; Lupski et al. 2010; Baets et al. 2011; Hoyer et al. 2014; Varley et al. 2015). The p.Arg954Ter variant is reported once in association with mononeuropathy of the median nerve. Lupski et al. (2010) report a family affected with autosomal recessive Charcot-Marie-Tooth, type 4 which includes three family members who are heterozygous for the p.Arg954Ter variant and present with a subtle mild mononeuropathy of the median nerve. The p.Arg954Ter variant has been shown to segregate with disease in a recessive inheritance pattern in at least two families (Lupski et al. 2010; Varley et al. 2015). The variant was reported in five of 180 controls in a heterozygous state, consistent with carrier status, and at a frequency of 0.00141 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and potential impact of stop-gained variants, the p.Arg954Ter variant is classified as pathogenic for SH3TC2-related disorders. It is most frequently described in association with autosomal recessive Charcot-Marie-Tooth, type 4, but has also been described in association with a mild presentation of dominantly inherited mononeuropathy of the median nerve. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jan 22, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Charcot-Marie-Tooth disease type 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001162825.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Clinical Features: Distal muscle weakness (present) , Respiratory insufficiency (present) , Sensorimotor neuropathy (present) Zygosity: Compound Heterozygote Sex: female Tissue: blood
Pathogenic (Feb 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mononeuropathy of the median nerve, mild Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448826.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Tall stature (present) , Childhood-onset truncal obesity (present) , Global developmental delay (present) , Macrocephalus (present) , Nystagmus (present) , Severe Myopia (present) , High, … (more) Tall stature (present) , Childhood-onset truncal obesity (present) , Global developmental delay (present) , Macrocephalus (present) , Nystagmus (present) , Severe Myopia (present) , High, narrow palate (present) , Clinodactyly of the 5th finger (present) , Abnormality of brain morphology (present) , Cerebral venous angioma (present) , Clonus (present) , Intellectual disability, moderate (present) (less) Sex: female
Likely pathogenic (Dec 15, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449826.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Pathogenic (Jul 21, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157366.3 First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022	Comment: The SH3TC2 c.2860C>T; p.Arg954Ter variant (rs80338933) has been reported in the homozygous and compound heterozygous states in multiple families and individuals diagnosed with Charcot-Marie-Tooth disease … (more) The SH3TC2 c.2860C>T; p.Arg954Ter variant (rs80338933) has been reported in the homozygous and compound heterozygous states in multiple families and individuals diagnosed with Charcot-Marie-Tooth disease type 4C (CMT4C) and was determined to be the most prevalent pathogenic variant in a cohort of CMT4C patients from the Czech Republic (Baets 2011, Høyer 2014, Laššuthová 2011, Lupski 2010, Senderek 2003, Varley 2015). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.12% in the non-Finnish European population (identified in 158 out of 126,576 chromosomes), and is classified as pathogenic in ClinVar (Variant ID: 2482). The p.Arg954Ter variant introduces a premature stop codon in exon 11 and is expected to result in a truncated or absent protein product. Therefore, based on the available evidence, the p.Arg954Ter variant is classified as pathogenic. Baets et al. Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain. 2011 Sep;134(Pt 9):2664-76. doi: 10.1093/brain/awr184. Epub 2011 Aug 11. Hoyer et al. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. Biomed Res Int. 2014;2014:210401. doi: 10.1155/2014/210401. Epub 2014 Jun 16. Lassuthova et al. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin Genet. 2011 Oct;80(4):334-45. doi: 10.1111/j.1399-0004.2011.01640.x. Epub 2011 Mar 1. Lupski et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010 Apr 1;362(13):1181-91. doi: 10.1056/NEJMoa0908094. Epub 2010 Mar 10. Senderek et al. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am J Hum Genet. 2003 Nov;73(5):1106-19. Epub 2003 Oct 21. Varley et al. Phenotypic variability of CMT4C in a French-Canadian kindred. Muscle Nerve. 2015 Sep;52(3):444-9. doi: 10.1002/mus.24640. Epub 2015 May 14. (less)
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Susceptibility to mononeuropathy of the median nerve, mild Affected status: yes Allele origin: germline	DASA Accession: SCV002061216.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (7) PubMed: 31346473‚ 30653784‚ 27231023‚ 25737037‚ 25326637‚ 25025039‚ 23806086 Comment: The c.2860C>T;p.(Arg954) variant creates a premature translational stop signal in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product … (more) The c.2860C>T;p.(Arg954) variant creates a premature translational stop signal in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(Clinvar ID: 2482; PMID: 31346473; 30653784; 27231023; 25737037; 25326637; 25025039; 23806086) - PS4. The p.(Arg954*) was detected in trans with a pathogenic variant (PMID: 31346473; 30653784; 27231023; PMID: 25737037; 25326637; 25025039; 23806086) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 25737037; 23806086) - PP1_strong and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: yes Allele origin: germline	3billion Accession: SCV002573214.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 14574644 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.073%). Stop-gained (nonsense) is predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.073%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002482 / PMID: 14574644 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Cerebellar ataxia (present) , Peripheral neuropathy (present) Zygosity: Homozygote
Pathogenic (Feb 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV002577561.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Comment: PVS1, PM2, PM3, PP5
Pathogenic (Feb 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556765.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Publications: PubMed (3) PubMed: 14574644‚ 20220177‚ 25737037 Comment: The SH3TC2 c.2860C>T variant is classified as PATHOGENIC (PVS1, PS4, PM3, PP1) The SH3TC2 c.2860C>T variant is a single nucleotide change which is predicted to … (more) The SH3TC2 c.2860C>T variant is classified as PATHOGENIC (PVS1, PS4, PM3, PP1) The SH3TC2 c.2860C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 954 (PVS1). This recurrent variant has been previously reported in both homozygous state or as compound heterozygotes with another pathogenic variant in SH3TC2 in patients with CMT4C (PMID:14574644, 20220177) (PS4, PM3). This variant has been reported to co-segregate with disease (PMID:25737037) (PP1). this variant has been reported in dbSNP (rs80338933) and has been reported in population databases (gnomAD 98/152176, no homozygotes). This variant has been reported in ClinVar as pathogenic for CMT4C by multiple other diagnostic laboratories (ClinVar Variation ID:2482) and is damaging in HGMD for CMT4C (CM033084). (less)
Pathogenic (Apr 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Susceptibility to mononeuropathy of the median nerve, mild Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611317.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (Sep 28, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321943.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21840889, 18511281, 28981955, 29243538, 30001926, 28726809, 29653220, 30653784, 30373780, 16924012, 25737037, 23806086, 20220177, 25525159, 25025039, 27231023, 19272779, 27549087, 27296017, 14574644, 29321516, 21291453, 31028937, 31346473, 31634715, 31827005, 31980526, 33386210, 25736553, 34426522, 34169998, 32376792, 31589614, 33643188, 32909314, 33726816) (less)
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004021208.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (1) PubMed: 30653784 Comment: Variant summary: SH3TC2 c.2860C>T (p.Arg954X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more) Variant summary: SH3TC2 c.2860C>T (p.Arg954X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00075 in 251330 control chromosomes. c.2860C>T has been reported in the literature in many individuals affected with Charcot-Marie Disease Type 4C (e.g. Kontogeorgiou_2019), including individuals who were reported as compound heterozygous with another pathogenic variant. These report(s) suggest the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30653784). 24 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jul 07, 2021)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000255843.5 First in ClinVar: Oct 19, 2015 Last updated: Jan 26, 2024	Publications: PubMed (5) PubMed: 14574644‚ 19272779‚ 16924012‚ 19744956‚ 23806086 Comment: This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more) This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000219133.14 First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 28492532‚ 20220177‚ 27068304‚ 14574644‚ 16924012‚ 18511281‚ 19272779 Comment: This sequence change creates a premature translational stop signal (p.Arg954) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg954) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs80338933, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 14574644, 16924012, 18511281, 19272779). It is commonly reported in individuals of French-Canadian ancestry (PMID: 18511281). ClinVar contains an entry for this variant (Variation ID: 2482). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 23, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000741997.5 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 14574644‚ 19744956‚ 20220177‚ 21840889‚ 25025039‚ 27549087 Comment: The c.2860C>T (p.R954) alteration, located in exon 11 (coding exon 11) of the SH3TC2 gene, consists of a C to T substitution at nucleotide position … (more) The c.2860C>T (p.R954) alteration, located in exon 11 (coding exon 11) of the SH3TC2 gene, consists of a C to T substitution at nucleotide position 2860. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 954. Premature stop codons are typically deleterious in nature (Richards, 2015). Based on data from gnomAD, the T allele has an overall frequency of 0.073% (206/282718) total alleles studied. The highest observed frequency was 0.125% (9/7224) of Other alleles. This alteration has been reported either homozygous or compound heterozygous with another SH3TC2 variant in multiple individuals with Charcot-Marie-Tooth (CMT) disease and presenting with similar symptoms as the proband (Senderek, 2003; Lupski, 2010; Baets, 2011; Høyer, 2014; La&scaron;&scaron;uthová, 2016). This mutation is reported to cause CMT1 in several different populations (Høyer, 2014). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Oct 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440841.2 First in ClinVar: Oct 30, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4_MOD,PM3_SUP Clinical Features: Demyelinating sensory neuropathy (present) , Sensory neuropathy (present) , Peripheral neuropathy (present) , Demyelinating peripheral neuropathy (present) , Demyelinating motor neuropathy (present) , Peripheral axonal … (more) Demyelinating sensory neuropathy (present) , Sensory neuropathy (present) , Peripheral neuropathy (present) , Demyelinating peripheral neuropathy (present) , Demyelinating motor neuropathy (present) , Peripheral axonal degeneration (present) (less) Sex: female
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005397997.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (3) PubMed: 20220177‚ 31393079‚ 32153140 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, type 4C (CMT) (MIM#601596). The mechanism of disease for mild mononeuropathy of the median nerve (MIM#613353) is unknown however, gain of function has been suggested (PMID: 20220177). (I) 0108 - This gene is associated with both recessive and dominant disease. CMT is caused by biallelic variants, while autosomal dominant mild mononeuropathy of the median nerve is rare and has been reported in one family (OMIM, PMID: 20220177). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (206 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported in patients with neuromuscular disease (DECIPHER, PMID: 32153140). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many homozygous and compound heterozygous patients with CMT, or rarely with a demyelinating neuropathy with hearing loss (ClinVar, PMID: 31393079). This variant has also been reported in several heterozygous carriers with very mild median nerve mononeuropathy, however more evidence is required to establish this genotype-phenotype association (PMID: 20220177). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Sep 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249577.27 First in ClinVar: May 09, 2020 Last updated: Dec 22, 2024	Comment: SH3TC2: PM3:Very Strong, PVS1, PM2, PP4 Number of individuals with the variant: 13
Pathogenic (Aug 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002520029.2 First in ClinVar: May 21, 2022 Last updated: Dec 28, 2024
Pathogenic (Dec 26, 2023)	no assertion criteria provided Method: clinical testing	SH3TC2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004765919.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The SH3TC2 c.2860C>T variant is predicted to result in premature protein termination (p.Arg954). This variant has been reported in the compound heterozygous and homozygous state … (more) The SH3TC2 c.2860C>T variant is predicted to result in premature protein termination (p.Arg954). This variant has been reported in the compound heterozygous and homozygous state to be causative for Charcot-Marie-Tooth disease (Baets et al. 2011. PubMed ID: 21840889; Høyer et al. 2014. PubMed ID: 25025039; Lupski et al. 2010. PubMed ID: 20220177). Although individuals heterozygous for the c.2860C>T (p.Arg954*) variant did not have Charcot-Marie-Tooth disease, they were reported to be at increased risk for developing neuropathy including carpal tunnel syndrome (Lupski et al. 2010. PubMed ID: 20220177). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in SH3TC2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Nov 01, 2013)	no assertion criteria provided Method: research	Charcot-Marie-Tooth disease Affected status: yes Allele origin: biparental	Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust Study: Charcot-Marie-Tooth disease study Accession: SCV000172149.1 First in ClinVar: Nov 09, 2014 Last updated: Nov 09, 2014 Comment: Populational based study of Charcot-Marie-Tooth disease in Norway	Publications: PubMed (5) PubMed: 14574644‚ 16924012‚ 18511281‚ 19272779‚ 25025039 pmc: 4306395 pmc: 4306395 Comment: Observed in four sporadic individuals Clinical Features: demyelinating type\|scoliosis (present) Comment on evidence: observed homozygote
Pathogenic (Apr 01, 2010)	no assertion criteria provided Method: literature only	MONONEUROPATHY OF THE MEDIAN NERVE, MILD Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022745.4 First in ClinVar: Apr 04, 2013 Last updated: Aug 15, 2020	Publications: PubMed (5) PubMed: 14574644‚ 16924012‚ 18511281‚ 19272779‚ 20220177 Comment on evidence: In 3 affected sibs from a German family with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified compound heterozygosity for 2 nonsense … (more) In 3 affected sibs from a German family with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified compound heterozygosity for 2 nonsense mutations in exon 11 of the SH3TC2 gene: a 2860C-T transition, resulting in an arg954-to-ter mutation (R954X; 608206.0005), and the Y943X mutation (608206.0004). Azzedine et al. (2006) reported that the R954X mutation was recurrent in their patient series, identified in 4 Dutch families and 1 Algerian family with CMT4C. In a French Canadian cluster of 17 CMT4C patients from Quebec, Canada, Gosselin et al. (2008) identified the R954X mutation in homozygosity in 12 patients from 7 families and in compound heterozygosity with an unidentified mutation in 2 patients from 1 family. In total, the R954X mutation was identified in 26 (76%) of 34 alleles from 10 families. Thirteen patients, including 10 homozygous for R954X, originated from a series of coastal villages in the Gaspesie, a sparsely populated peninsular region of Quebec, near the Maine/U.S. border. The villages are distributed along a 150-km stretch of the western shore of Chaleur Bay. Haplotype analysis demonstrated that at least 2 distinct CMT4C mutations are present in the French Canadian population and indicated a founder effect for the R954X mutation. Houlden et al. (2009) identified a homozygous R954X mutation in affected members of 4 English families with CMT4C. A fifth English family was compound heterozygous for R954X and a 1969G-A transition, resulting in a gly657-to-lys substitution (E657K; 608206.0007). There was significant phenotypic variability between these families: some presented with severe childhood onset, respiratory and cranial nerve involvement, and became wheelchair-bound, whereas others had only mild scoliosis and foot deformity. One patient homozygous for the R954X mutation had a superimposed inflammatory neuropathy associated with steroid treatment for ulcerative colitis. In 4 sibs with CMT4C, Lupski et al. (2010) identified compound heterozygosity for 2 mutations in the SH3TC2 gene: R954X and Y169H (608206.0008). Three additional family members who were heterozygous for the R954X mutation had a mild mononeuropathy of the median nerve (MNMN; 613353) consistent with carpal tunnel syndrome. Lupski et al. (2010) concluded that haploinsufficiency of SH3TC2 may confer susceptibility to carpal tunnel syndrome. (less)
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Charcot-Marie-Tooth disease type 4C Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760156.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921051.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932585.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953960.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971522.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Apr 01, 2010)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4C Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022744.5 First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2024	Publications: PubMed (5) PubMed: 14574644‚ 16924012‚ 18511281‚ 19272779‚ 20220177 Comment on evidence: In 3 affected sibs from a German family with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified compound heterozygosity for 2 nonsense … (more) In 3 affected sibs from a German family with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified compound heterozygosity for 2 nonsense mutations in exon 11 of the SH3TC2 gene: a 2860C-T transition, resulting in an arg954-to-ter mutation (R954X; 608206.0005), and the Y943X mutation (608206.0004). Azzedine et al. (2006) reported that the R954X mutation was recurrent in their patient series, identified in 4 Dutch families and 1 Algerian family with CMT4C. In a French Canadian cluster of 17 CMT4C patients from Quebec, Canada, Gosselin et al. (2008) identified the R954X mutation in homozygosity in 12 patients from 7 families and in compound heterozygosity with an unidentified mutation in 2 patients from 1 family. In total, the R954X mutation was identified in 26 (76%) of 34 alleles from 10 families. Thirteen patients, including 10 homozygous for R954X, originated from a series of coastal villages in the Gaspesie, a sparsely populated peninsular region of Quebec, near the Maine/U.S. border. The villages are distributed along a 150-km stretch of the western shore of Chaleur Bay. Haplotype analysis demonstrated that at least 2 distinct CMT4C mutations are present in the French Canadian population and indicated a founder effect for the R954X mutation. Houlden et al. (2009) identified a homozygous R954X mutation in affected members of 4 English families with CMT4C. A fifth English family was compound heterozygous for R954X and a 1969G-A transition, resulting in a gly657-to-lys substitution (E657K; 608206.0007). There was significant phenotypic variability between these families: some presented with severe childhood onset, respiratory and cranial nerve involvement, and became wheelchair-bound, whereas others had only mild scoliosis and foot deformity. One patient homozygous for the R954X mutation had a superimposed inflammatory neuropathy associated with steroid treatment for ulcerative colitis. In 4 sibs with CMT4C, Lupski et al. (2010) identified compound heterozygosity for 2 mutations in the SH3TC2 gene: R954X and Y169H (608206.0008). Three additional family members who were heterozygous for the R954X mutation had a mild mononeuropathy of the median nerve (MNMN; 613353) consistent with carpal tunnel syndrome. Lupski et al. (2010) concluded that haploinsufficiency of SH3TC2 may confer susceptibility to carpal tunnel syndrome. (less)
not provided (-)	no classification provided Method: phenotyping only	Charcot-Marie-Tooth disease type 4C Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749922.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Pathogenic and reported on 07-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more) Variant interpreted as Pathogenic and reported on 07-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2019-07-19 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Charcot-Marie-Tooth disease type 4C Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000041492.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (10) PubMed: 20301514‚ 16924012‚ 16806930‚ 19272779‚ 21840889‚ 21291453‚ 21892769‚ 27231023‚ 30653784‚ 31346473 BookShelf: NBK1340 BookShelf: NBK1340
Pathogenic (Oct 26, 2021)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Notes: This gene has (...more) Source: ClinGen	Tip-toe gait Affected status: yes Allele origin: germline	Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino Accession: SCV002106407.2 First in ClinVar: Mar 28, 2022 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 37091313 DOI: 10.3238/oup.2019.0380-0382 DOI: 10.3238/oup.2019.0380-0382 Comment: Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, … (more) Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. (less) Clinical Features: Pes cavus (present) , Brachydactyly (present) , Clinodactyly (present) , limited range of motion of the upper ankle (present) Age: 10-19 years Sex: male Method: Gene panel analysis
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Comment:

DNA sequence analysis of the SH3TC2 gene demonstrated a sequence change, c.2860C>T, which results in the creation of a premature stop codon at amino acid position 954, p.Arg954*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SH3TC2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple patients with SH3TC2-related Charcot-Marie-Tooth disease type 4C (Senderek et al., 2003; Houlden et al., 2009.).

Comment:

The SH3TC2 c.2860C>T (p.Arg954Ter) variant is a stop-gained variant and is predicted to result in premature termination of the protein. The p.Arg954Ter variant is reported in at least nine studies associated with Charcot-Marie-Tooth, type 4, and found in a total of 39 unrelated patients including 26 homozygotes and 13 compound heterozygote (Senderek et al. 2003; Azzedine et al. 2006; Lupo et al. 2009; Gosselin et al. 2008; Houlden et al. 2009; Lupski et al. 2010; Baets et al. 2011; Hoyer et al. 2014; Varley et al. 2015). The p.Arg954Ter variant is reported once in association with mononeuropathy of the median nerve. Lupski et al. (2010) report a family affected with autosomal recessive Charcot-Marie-Tooth, type 4 which includes three family members who are heterozygous for the p.Arg954Ter variant and present with a subtle mild mononeuropathy of the median nerve. The p.Arg954Ter variant has been shown to segregate with disease in a recessive inheritance pattern in at least two families (Lupski et al. 2010; Varley et al. 2015). The variant was reported in five of 180 controls in a heterozygous state, consistent with carrier status, and at a frequency of 0.00141 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and potential impact of stop-gained variants, the p.Arg954Ter variant is classified as pathogenic for SH3TC2-related disorders. It is most frequently described in association with autosomal recessive Charcot-Marie-Tooth, type 4, but has also been described in association with a mild presentation of dominantly inherited mononeuropathy of the median nerve. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The SH3TC2 c.2860C>T; p.Arg954Ter variant (rs80338933) has been reported in the homozygous and compound heterozygous states in multiple families and individuals diagnosed with Charcot-Marie-Tooth disease type 4C (CMT4C) and was determined to be the most prevalent pathogenic variant in a cohort of CMT4C patients from the Czech Republic (Baets 2011, Høyer 2014, Laššuthová 2011, Lupski 2010, Senderek 2003, Varley 2015). This variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.12% in the non-Finnish European population (identified in 158 out of 126,576 chromosomes), and is classified as pathogenic in ClinVar (Variant ID: 2482). The p.Arg954Ter variant introduces a premature stop codon in exon 11 and is expected to result in a truncated or absent protein product. Therefore, based on the available evidence, the p.Arg954Ter variant is classified as pathogenic. Baets et al. Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain. 2011 Sep;134(Pt 9):2664-76. doi: 10.1093/brain/awr184. Epub 2011 Aug 11. Hoyer et al. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. Biomed Res Int. 2014;2014:210401. doi: 10.1155/2014/210401. Epub 2014 Jun 16. Lassuthova et al. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin Genet. 2011 Oct;80(4):334-45. doi: 10.1111/j.1399-0004.2011.01640.x. Epub 2011 Mar 1. Lupski et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010 Apr 1;362(13):1181-91. doi: 10.1056/NEJMoa0908094. Epub 2010 Mar 10. Senderek et al. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am J Hum Genet. 2003 Nov;73(5):1106-19. Epub 2003 Oct 21. Varley et al. Phenotypic variability of CMT4C in a French-Canadian kindred. Muscle Nerve. 2015 Sep;52(3):444-9. doi: 10.1002/mus.24640. Epub 2015 May 14.

Comment:

The c.2860C>T;p.(Arg954*) variant creates a premature translational stop signal in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(Clinvar ID: 2482; PMID: 31346473; 30653784; 27231023; 25737037; 25326637; 25025039; 23806086) - PS4. The p.(Arg954*) was detected in trans with a pathogenic variant (PMID: 31346473; 30653784; 27231023; PMID: 25737037; 25326637; 25025039; 23806086) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 25737037; 23806086) - PP1_strong and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.073%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002482 / PMID: 14574644 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The SH3TC2 c.2860C>T variant is classified as PATHOGENIC (PVS1, PS4, PM3, PP1) The SH3TC2 c.2860C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 954 (PVS1). This recurrent variant has been previously reported in both homozygous state or as compound heterozygotes with another pathogenic variant in SH3TC2 in patients with CMT4C (PMID:14574644, 20220177) (PS4, PM3). This variant has been reported to co-segregate with disease (PMID:25737037) (PP1). this variant has been reported in dbSNP (rs80338933) and has been reported in population databases (gnomAD 98/152176, no homozygotes). This variant has been reported in ClinVar as pathogenic for CMT4C by multiple other diagnostic laboratories (ClinVar Variation ID:2482) and is damaging in HGMD for CMT4C (CM033084).

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21840889, 18511281, 28981955, 29243538, 30001926, 28726809, 29653220, 30653784, 30373780, 16924012, 25737037, 23806086, 20220177, 25525159, 25025039, 27231023, 19272779, 27549087, 27296017, 14574644, 29321516, 21291453, 31028937, 31346473, 31634715, 31827005, 31980526, 33386210, 25736553, 34426522, 34169998, 32376792, 31589614, 33643188, 32909314, 33726816)

Comment:

Variant summary: SH3TC2 c.2860C>T (p.Arg954X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00075 in 251330 control chromosomes. c.2860C>T has been reported in the literature in many individuals affected with Charcot-Marie Disease Type 4C (e.g. Kontogeorgiou_2019), including individuals who were reported as compound heterozygous with another pathogenic variant. These report(s) suggest the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30653784). 24 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg954*) in the SH3TC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs80338933, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 14574644, 16924012, 18511281, 19272779). It is commonly reported in individuals of French-Canadian ancestry (PMID: 18511281). ClinVar contains an entry for this variant (Variation ID: 2482). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.2860C>T (p.R954*) alteration, located in exon 11 (coding exon 11) of the SH3TC2 gene, consists of a C to T substitution at nucleotide position 2860. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 954. Premature stop codons are typically deleterious in nature (Richards, 2015). Based on data from gnomAD, the T allele has an overall frequency of 0.073% (206/282718) total alleles studied. The highest observed frequency was 0.125% (9/7224) of Other alleles. This alteration has been reported either homozygous or compound heterozygous with another SH3TC2 variant in multiple individuals with Charcot-Marie-Tooth (CMT) disease and presenting with similar symptoms as the proband (Senderek, 2003; Lupski, 2010; Baets, 2011; Høyer, 2014; La&scaron;&scaron;uthová, 2016). This mutation is reported to cause CMT1 in several different populations (Høyer, 2014). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, type 4C (CMT) (MIM#601596). The mechanism of disease for mild mononeuropathy of the median nerve (MIM#613353) is unknown however, gain of function has been suggested (PMID: 20220177). (I) 0108 - This gene is associated with both recessive and dominant disease. CMT is caused by biallelic variants, while autosomal dominant mild mononeuropathy of the median nerve is rare and has been reported in one family (OMIM, PMID: 20220177). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (206 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported in patients with neuromuscular disease (DECIPHER, PMID: 32153140). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many homozygous and compound heterozygous patients with CMT, or rarely with a demyelinating neuropathy with hearing loss (ClinVar, PMID: 31393079). This variant has also been reported in several heterozygous carriers with very mild median nerve mononeuropathy, however more evidence is required to establish this genotype-phenotype association (PMID: 20220177). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The SH3TC2 c.2860C>T variant is predicted to result in premature protein termination (p.Arg954*). This variant has been reported in the compound heterozygous and homozygous state to be causative for Charcot-Marie-Tooth disease (Baets et al. 2011. PubMed ID: 21840889; Høyer et al. 2014. PubMed ID: 25025039; Lupski et al. 2010. PubMed ID: 20220177). Although individuals heterozygous for the c.2860C>T (p.Arg954*) variant did not have Charcot-Marie-Tooth disease, they were reported to be at increased risk for developing neuropathy including carpal tunnel syndrome (Lupski et al. 2010. PubMed ID: 20220177). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in SH3TC2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.

Comment:

Variant interpreted as Pathogenic and reported on 07-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly.	Pomarino D	Global medical genetics	2023	PMID: 37091313
SH3TC2-Related Hereditary Motor and Sensory Neuropathy.	Adam MP	-	2021	PMID: 20301514
Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience.	Beecroft SJ	Annals of clinical and translational neurology	2020	PMID: 32153140
Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series.	Lerat J	Molecular genetics & genomic medicine	2019	PMID: 31393079
The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.	Skott H	Cerebellum & ataxias	2019	PMID: 31346473
Mutational screening of the SH3TC2 gene in Greek patients with suspected demyelinating recessive Charcot-Marie-Tooth disease reveals a varied and unusual phenotypic spectrum.	Kontogeorgiou Z	Journal of the peripheral nervous system : JPNS	2019	PMID: 30653784
Improving diagnosis of inherited peripheral neuropathies through gene panel analysis.	Laššuthová P	Orphanet journal of rare diseases	2016	PMID: 27549087
Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4).	Piscosquito G	Journal of the peripheral nervous system : JPNS	2016	PMID: 27231023
Exclusive expression of the Rab11 effector SH3TC2 in Schwann cells links integrin-α6 and myelin maintenance to Charcot-Marie-Tooth disease type 4C.	Vijay S	Biochimica et biophysica acta	2016	PMID: 27068304
Phenotypic variability of CMT4C in a French-Canadian kindred.	Varley TL	Muscle & nerve	2015	PMID: 25737037
Clinical exome sequencing for genetic identification of rare Mendelian disorders.	Lee H	JAMA	2014	PMID: 25326637
Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing.	Høyer H	BioMed research international	2014	PMID: 25025039
Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy.	Lupski JR	Genome medicine	2013	PMID: 23806086
SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease.	Fischer C	Journal of neurology	2012	PMID: 21892769
Genetic spectrum of hereditary neuropathies with onset in the first year of life.	Baets J	Brain : a journal of neurology	2011	PMID: 21840889
High frequency of SH3TC2 mutations in Czech HMSN I patients.	Laššuthová P	Clinical genetics	2011	PMID: 21291453
Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy.	Lupski JR	The New England journal of medicine	2010	PMID: 20220177
Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway.	Lupo V	Human molecular genetics	2009	PMID: 19744956
The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy.	Houlden H	Neuromuscular disorders : NMD	2009	PMID: 19272779
Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster.	Gosselin I	Neuromuscular disorders : NMD	2008	PMID: 18511281
Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.	Azzedine H	Neurology	2006	PMID: 16924012
Clinical spectrum of CMT4C disease in patients homozygous for the p.Arg1109X mutation in SH3TC2.	Colomer J	Neuromuscular disorders : NMD	2006	PMID: 16806930
Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.	Senderek J	American journal of human genetics	2003	PMID: 14574644
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SH3TC2	-	-	-	-
-	-	-	-	DOI: 10.3238/oup.2019.0380-0382
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Text-mined citations for rs80338933 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 28, 2024

ClinVar Genomic variation as it relates to human health

NM_024577.4(SH3TC2):c.2860C>T (p.Arg954Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338933 ...