VCV002579221.1 - ClinVar

GRCh38/hg38 15q15.1(chr15:42349336-42378932)x1

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

GRCh38/hg38 15q15.1(chr15:42349336-42378932)x1

Variation ID: 2579221 Accession: VCV002579221.1

Type and length

copy number loss, 29,597 bp

Location

Cytogenetic: 15q15.1 15: 42349336-42378932 (GRCh38) [ 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	Sep 16, 2023	Sep 16, 2023	Aug 24, 2023

HGVS

Protein change

Other names

Canonical SPDI

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.
CAPN3		-	-	GRCh38 GRCh37	1739	1881
GANC		-	-	GRCh38 GRCh37	46	67

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.
Autosomal recessive limb-girdle muscular dystrophy type 2A	Pathogenic (1)	criteria provided, single submitter	Aug 24, 2023	RCV003327660.2

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.
Pathogenic (Aug 24, 2023)	criteria provided, single submitter (ACMG/ClinGen CNV Guidelines, 2019) Method: research	Autosomal recessive limb-girdle muscular dystrophy type 2A (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV004034194.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Publications: PubMed (3) PubMed: 31690835‚ 32528171‚ 31501033 Comment: A heterozygous deletion of exon 1 in CAPN3 (NM_000070.3) was identified by exome sequencing and confirmed by genome sequencing in one individual with limb-girdle muscular … (more) A heterozygous deletion of exon 1 in CAPN3 (NM_000070.3) was identified by exome sequencing and confirmed by genome sequencing in one individual with limb-girdle muscular dystrophy in the compound heterozygous state, along with a variant of uncertain significance (VariationID: 282623)([GRCh 38] chr15:42349336_42378932x1)(PMID: 32528171). Inheritance information is unavailable. The patient phenotype is nonspecific, but is consistent with cases described in the literature and/or published databases with overlapping variants. This intragenic variant deletes the first coding exon and is predicted to cause loss of the methionine initiation codon. There is no in frame methionine in exon 2 or 3 that could reinitiate translation. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy (https://search.thegencc.org/genes). In vitro functional studies provide some evidence that the exon 1 deletion variant may impact protein function (PMID: 31501033). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant limb-girdle muscular dystrophy. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.90 points, 3: 0 points, 4-5: 0.8 points; Function data: 0.15; Total: 1.13 points; Riggs 2020 (PMID: 31690835). (less)

Comment:

A heterozygous deletion of exon 1 in CAPN3 (NM_000070.3) was identified by exome sequencing and confirmed by genome sequencing in one individual with limb-girdle muscular dystrophy in the compound heterozygous state, along with a variant of uncertain significance (VariationID: 282623)([GRCh 38] chr15:42349336_42378932x1)(PMID: 32528171). Inheritance information is unavailable. The patient phenotype is nonspecific, but is consistent with cases described in the literature and/or published databases with overlapping variants. This intragenic variant deletes the first coding exon and is predicted to cause loss of the methionine initiation codon. There is no in frame methionine in exon 2 or 3 that could reinitiate translation. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy (https://search.thegencc.org/genes). In vitro functional studies provide some evidence that the exon 1 deletion variant may impact protein function (PMID: 31501033). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant limb-girdle muscular dystrophy. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.90 points, 3: 0 points, 4-5: 0.8 points; Function data: 0.15; Total: 1.13 points; Riggs 2020 (PMID: 31690835).

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
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.	Töpf A	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32528171
Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).	Riggs ER	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31690835
Gene Correction of LGMD2A Patient-Specific iPSCs for the Development of Targeted Autologous Cell Therapy.	Selvaraj S	Molecular therapy : the journal of the American Society of Gene Therapy	2019	PMID: 31501033

Text-mined citations for this variant ...

Record last updated Mar 30, 2024

ClinVar Genomic variation as it relates to human health

GRCh38/hg38 15q15.1(chr15:42349336-42378932)x1

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...