VCV000448370.37 - ClinVar

NM_024577.4(SH3TC2):c.3511C>T (p.Arg1171Cys)

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.

(12)

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.3511C>T (p.Arg1171Cys)

Variation ID: 448370 Accession: VCV000448370.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q32 5: 149007045 (GRCh38) [ NCBI UCSC ] 5: 148386608 (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	Dec 19, 2017	Apr 6, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024577.4:c.3511C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078853.2:p.Arg1171Cys	missense
NC_000005.10:g.149007045G>A
NC_000005.9:g.148386608G>A
NG_007947.2:g.61130C>T
LRG_269:g.61130C>T
LRG_269t1:c.3511C>T	LRG_269p1:p.Arg1171Cys

... more HGVS ... less HGVS

Protein change

R1171C

Other names

Canonical SPDI

NC_000005.10:149007044: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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA3498696 dbSNP: rs759785462 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	1759	1801

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.
not provided	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 16, 2024	RCV000517446.8
Charcot-Marie-Tooth disease type 4C	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000754746.6
Charcot-Marie-Tooth disease type 4	Pathogenic (1)	criteria provided, single submitter	Sep 4, 2023	RCV000805465.7
Charcot-Marie-Tooth disease	Likely pathogenic (2)	criteria provided, single submitter	-	RCV000790335.2
Peripheral neuropathy	Likely pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814180.1
SH3TC2-related disorder	not provided (1)	no classification provided	-	RCV003483649.1

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.
Likely pathogenic (Mar 28, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000615248.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (2) PubMed: 23466821‚ 25429913
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: unknown	NeuroMeGen, Hospital Clinico Santiago de Compostela Accession: SCV000882636.1 First in ClinVar: Feb 04, 2019 Last updated: Feb 04, 2019	Zygosity: Single Heterozygote
Likely 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: SCV001336227.1 First in ClinVar: Jun 15, 2020 Last updated: Jun 15, 2020
Likely 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: SCV001447203.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Acute demyelinating polyneuropathy (present) , Polyneuropathy (present) Sex: male
Likely pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peripheral neuropathy Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755646.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (-)	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	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048553.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The missense variant c.3511C>T (p.Arg1171Cys) has been previously observed as homozygous or in combination with another SH3TC2 variant in individuals affected with autosomal recessive Charcot-Marie-Tooth … (more) The missense variant c.3511C>T (p.Arg1171Cys) has been previously observed as homozygous or in combination with another SH3TC2 variant in individuals affected with autosomal recessive Charcot-Marie-Tooth disease (Hayashi et al. 2013). This variant disrupts the p.Arg1171 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue have been observed in affected individuals (Yger et al. 2012), which suggests that this may be a clinically significant amino acid residue. The p.Arg1171Cys variant is novel (not in any individuals) in 1000 Genomes. This variant is present in the ExAC population database with a frequency of 0.006%. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Likely Pathogenic/Uncertain Significance. The amino acid Arg at position 1171 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg1171Cys in SH3TC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less) Clinical Features: Lower limb muscle weakness (present) , Acute demyelinating polyneuropathy (present)
Likely pathogenic (Jan 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003819992.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Sep 04, 2023)	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: SCV000945422.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 23466821‚ 25429913‚ 30001926‚ 31130284‚ 22462672 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1171 of the SH3TC2 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1171 of the SH3TC2 protein (p.Arg1171Cys). This variant is present in population databases (rs759785462, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 23466821, 25429913, 30001926, 31130284). ClinVar contains an entry for this variant (Variation ID: 448370). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SH3TC2 protein function. This variant disrupts the p.Arg1171 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22462672; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Charcot-Marie-Tooth disease type 4C Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004801160.2 First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024
Uncertain significance (-)	no assertion criteria provided Method: literature only	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000929745.1 First in ClinVar: Jul 29, 2019 Last updated: Jul 29, 2019	Publications: PubMed (1) PubMed: 25429913
Uncertain significance (Jun 08, 2019)	no assertion criteria provided Method: clinical testing	Charcot-Marie-Tooth disease, type 4C (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences Accession: SCV001292402.1 First in ClinVar: Jun 15, 2020 Last updated: Jun 15, 2020	Comment: The patient was an 18-year-old male with difficulty climbing stairs since 7-year old. He had mild dysarthria, mild hypotonia, distal muscle weakness (legs>arms), claw hands, … (more) The patient was an 18-year-old male with difficulty climbing stairs since 7-year old. He had mild dysarthria, mild hypotonia, distal muscle weakness (legs>arms), claw hands, wasting of lower limbs, bilateral foot drop, and steppage gait. The electrodiagnostic study was in favor of a chronic demyelinating sensorimotor polyneuropathy. (less) Number of individuals with the variant: 1 Age: 10-19 years Sex: male Ethnicity/Population group: Iranian Geographic origin: Iran
not provided (-)	no classification provided Method: phenotyping only	SH3TC2-related disorder Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228681.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Pathogenic and reported on 06-03-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 06-03-2020 by Lab 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: Myopia (present) , Abnormal oral cavity morphology (present) , Abnormal skull morphology (present) , Atrophic scars (present) , Asthma (present) , Decreased pulmonary function (present) … (more) Myopia (present) , Abnormal oral cavity morphology (present) , Abnormal skull morphology (present) , Atrophic scars (present) , Asthma (present) , Decreased pulmonary function (present) , Respiratory insufficiency (present) , Abnormal pattern of respiration (present) , Abnormality of the upper respiratory tract (present) , Bruising susceptibility (present) , Persistent bleeding after trauma (present) , Abnormal erythrocyte morphology (present) , Autoimmunity (present) , Abnormal inflammatory response (present) , Recurrent infections (present) , Abnormal stomach morphology (present) , Obesity (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal limb bone morphology (present) , Abnormal curvature of the vertebral column (present) , Developmental dysplasia of the hip (present) , Precocious puberty (present) , Goiter (present) , Type 2 diabetes mellitus (present) , Abnormality of urine homeostasis (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Memory impairment (present) , Depression (present) , Hallucinations (present) , Motor stereotypies (present) (less) Indication for testing: Diagnostic Zygosity: Single Heterozygote Age: 50-59 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2020-06-03 Testing laboratory interpretation: Pathogenic
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Comment:

The missense variant c.3511C>T (p.Arg1171Cys) has been previously observed as homozygous or in combination with another SH3TC2 variant in individuals affected with autosomal recessive Charcot-Marie-Tooth disease (Hayashi et al. 2013). This variant disrupts the p.Arg1171 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue have been observed in affected individuals (Yger et al. 2012), which suggests that this may be a clinically significant amino acid residue. The p.Arg1171Cys variant is novel (not in any individuals) in 1000 Genomes. This variant is present in the ExAC population database with a frequency of 0.006%. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Likely Pathogenic/Uncertain Significance. The amino acid Arg at position 1171 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg1171Cys in SH3TC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1171 of the SH3TC2 protein (p.Arg1171Cys). This variant is present in population databases (rs759785462, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 23466821, 25429913, 30001926, 31130284). ClinVar contains an entry for this variant (Variation ID: 448370). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SH3TC2 protein function. This variant disrupts the p.Arg1171 amino acid residue in SH3TC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22462672; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

The patient was an 18-year-old male with difficulty climbing stairs since 7-year old. He had mild dysarthria, mild hypotonia, distal muscle weakness (legs>arms), claw hands, wasting of lower limbs, bilateral foot drop, and steppage gait. The electrodiagnostic study was in favor of a chronic demyelinating sensorimotor polyneuropathy.

Comment:

Variant interpreted as Pathogenic and reported on 06-03-2020 by Lab 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
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.	Monies D	American journal of human genetics	2019	PMID: 31130284
Charcot-Marie-Tooth disease type 4C in Norway: Clinical characteristics, mutation spectrum and minimum prevalence.	Arntzen KA	Neuromuscular disorders : NMD	2018	PMID: 30001926
Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population.	Manganelli F	Journal of the peripheral nervous system : JPNS	2014	PMID: 25429913
Molecular analysis of the genes causing recessive demyelinating Charcot-Marie-Tooth disease in Japan.	Hayashi M	Journal of human genetics	2013	PMID: 23466821
Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C.	Yger M	Journal of the peripheral nervous system : JPNS	2012	PMID: 22462672

Text-mined citations for rs759785462 ...

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 07, 2024

ClinVar Genomic variation as it relates to human health

NM_024577.4(SH3TC2):c.3511C>T (p.Arg1171Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs759785462 ...