Submissions for variant NM_000070.3(CAPN3):c.2332G>A (p.Asp778Asn)

gnomAD frequency: 0.00908  dbSNP: rs115311625

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078094	SCV000109932	benign	not specified	2012-08-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000078094	SCV000301879	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000078094	SCV000523001	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000499264	SCV000645495	benign	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000499264	SCV000793900	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-09-12	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000859376	SCV001143418	benign	not provided	2018-10-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000499264	SCV001277664	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078094	SCV003844589	benign	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.2332G>A (p.Asp778Asn) results in a conservative amino acid change located in the penta-EF-hand domain (IPR029531) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251396 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in CAPN3 causing an autosomal recessive Limb-Girdle Muscular Dystrophy phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2332G>A has been reported in the literature in the compound heterozygous state in one individual affected with Limb-Girdle Muscular Dystrophy (Pathak_2021). This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as benign (n=3)/likely benign (n=3) and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000078094	SCV000150496	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000499264	SCV000590902	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-08-16	flagged submission	clinical testing	This mutation has been reported in 1000 genomes and ExAC databases with minor allele frequency of 0.9% and 0.28%. The in silico prediction of this variant is damaging by Mutation Taster2.
Natera, Inc.	RCV000499264	SCV002085560	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2A	2019-11-11	no assertion criteria provided	clinical testing