VCV002840086.1 - ClinVar

NM_001005373.4(LRSAM1):c.2033_2038del (p.Cys678_Glu680delinsTer)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001005373.4(LRSAM1):c.2033_2038del (p.Cys678_Glu680delinsTer)

Variation ID: 2840086 Accession: VCV002840086.1

Type and length

Deletion, 6 bp

Location

Cytogenetic: 9q34.11 9: 127501130-127501135 (GRCh38) [ NCBI UCSC ] 9: 130263409-130263414 (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	Feb 20, 2024	Feb 20, 2024	Apr 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005373.4:c.2033_2038del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005373.1:p.Cys678_Glu680delinsTer	nonsense
NM_001005374.4:c.2033_2038del	NP_001005374.1:p.Cys678_Glu680delinsTer	nonsense
NM_001190723.3:c.1952_1957del	NP_001177652.1:p.Cys651_Glu653delinsTer	nonsense
NM_001384142.1:c.2033_2038del	NP_001371071.1:p.Cys678_Glu680delinsTer	nonsense
NM_001384143.1:c.1934_1939del	NP_001371072.1:p.Cys645_Glu647delinsTer	nonsense
NM_001384144.1:c.1244_1249del	NP_001371073.1:p.Cys415_Glu417delinsTer	nonsense
NM_138361.5:c.2033_2038del	NP_612370.3:p.Cys678_Glu680delinsTer	nonsense
NR_168891.1:n.2562_2567del		non-coding transcript variant
NR_168892.1:n.2386_2391del		non-coding transcript variant
NC_000009.12:g.127501130_127501135del
NC_000009.11:g.130263409_130263414del
NG_032008.1:g.54645_54650del
NG_117561.1:g.661_666del
LRG_373:g.54645_54650del
LRG_373t1:c.2033_2038del	LRG_373p1:p.Cys678_Glu680delinsTer

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000009.12:127501129:GCCTGG:

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.

Links

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.
LRSAM1		-	-	GRCh38 GRCh37	885	927

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 axonal type 2P	Likely pathogenic (1)	criteria provided, single submitter	Apr 29, 2023	RCV003644089.2

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 (Apr 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2P Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004499739.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 33414056‚ 31211173‚ 29341362 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This protein change is located in a region of the LRSAM1 protein where a significant number of LRSAM1 nonsense and frameshift mutations have been reported in autosomal dominant Charcot-Marie-Tooth disease (PMID: 33414056, 31211173, 29341362). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys678*) in the LRSAM1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the LRSAM1 protein. (less)

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This protein change is located in a region of the LRSAM1 protein where a significant number of LRSAM1 nonsense and frameshift mutations have been reported in autosomal dominant Charcot-Marie-Tooth disease (PMID: 33414056, 31211173, 29341362). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys678*) in the LRSAM1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the LRSAM1 protein.

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
Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P.	Reilich P	Neuromuscular disorders : NMD	2021	PMID: 33414056
Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan.	Hsu YH	Annals of clinical and translational neurology	2019	PMID: 31211173
A novel mutation of LRSAM1 in a Chinese family with Charcot-Marie-Tooth disease.	Zhao G	Journal of the peripheral nervous system : JPNS	2018	PMID: 29341362

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001005373.4(LRSAM1):c.2033_2038del (p.Cys678_Glu680delinsTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...