Submissions for variant NM_000070.3(CAPN3):c.2338G>C (p.Asp780His)

gnomAD frequency: 0.00001  dbSNP: rs778768583

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000386470	SCV000227875	pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000386470	SCV000329194	pathogenic	not provided	2018-01-15	criteria provided, single submitter	clinical testing	The D780H missense variant in the CAPN3 gene has been reported previously as a founder mutation in the Agarwal Eastern Indian population in individuals with LGMD2A (Ankala, et al., 2013; Todorova et al., 2005). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with limb-girdle muscular dystrophy (Stenson et al., 2014). The D780H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, we interpret D780H as a pathogenic variant.
Athena Diagnostics Inc	RCV000386470	SCV000612640	pathogenic	not provided	2017-04-17	criteria provided, single submitter	clinical testing
Invitae	RCV000176251	SCV000766714	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 780 of the CAPN3 protein (p.Asp780His). This variant is present in population databases (rs778768583, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 15733273, 23666804, 25079074, 27011640). It is commonly reported in individuals of Agarwal North Indian ancestry (PMID: 15733273, 23666804, 25079074, 27011640). ClinVar contains an entry for this variant (Variation ID: 195641). 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 CAPN3 protein function. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000176251	SCV001164527	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Asp780His variant in CAPN3 was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.0008124% (2/246172) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778768583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The variant is located in the well-established functional domain EF-hand 4, a domain involved in protein homodimerization (PMID: 24846670). In vitro functional studies with muscle biopsies provide some evidence that the p.Asp780His variant may impact protein function by reducing translation and autolytic activity (PMID: 25079074). However, these types of assays may not accurately represent biological function. The p.Asp780His variant in CAPN3 has been reported in 7 Indian Agarwal individuals with LGMD and is a known founder mutation in the Indian Agarwal community (PMID: 23666804). The presence of this variant in combination with a pathogenic variant by our study as well as a splice site variant in 5 individuals with LGMD increases the likelihood that the p.Asp780His variant is pathogenic (PMID: 23666804). This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 195641). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on its location in a well-established functional domain and multiple occurrences with other CAPN3 variants. ACMG/AMP Criteria applied: PM2, PP3, PM1, PS3_Supporting, PM3_Strong (Richards 2015).
Revvity Omics, Revvity	RCV000386470	SCV002018046	pathogenic	not provided	2023-09-06	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000176251	SCV002073079	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A		criteria provided, single submitter	clinical testing	The missense variant NM_000070.3(CAPN3):c.2338G>C (p.Asp780His) has been previously reported as an Aggarwal Founder mutation for Calpainopathy (Ankala et al; Khadilkar et al). Experimental studies have shown that this missense change results in reduced protein expression and autolytic activity in muscle biopsy samples (Nilsson MI et al). It has been classified as Pathogenic/Likely Pathogenic in the ClinVar database. The p.Asp780His variant is observed in 1/30,616 (0.0033%) alleles from individuals of gnomAD South Asian background in gnomAD and is novel in the 1000 Genomes. There is a moderate physicochemical difference between aspartic acid and histidine. The p.Asp780His missense variant is predicted to be damaging by both SIFT and PolyPhen2. The aspartic acid residue at codon 780 of CAPN3 is conserved in all mammalian species. The nucleotide c.2338 in CAPN3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003474930	SCV004211524	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-10-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000176251	SCV000789634	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-02-08	no assertion criteria provided	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000176251	SCV000844967	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-09-18	no assertion criteria provided	clinical testing	The observed variant c.2338G>C (p.Asp780His) has not been reported in 1000 Genomes and has a minor allele frequency of 0.002% in the ExAC databases. The In silico prediction of the given variant is probably damaging by PolyPhen-2 and damaging by MutationTaster2 and SIFT. The above variant was observed as compound heterozygous along with the variant g.50431G>T (3'splice site). The variant g.50431G>T (3'splice site) has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is damaging by MutationTaster2.
GeneReviews	RCV000176251	SCV002015206	not provided	Autosomal recessive limb-girdle muscular dystrophy type 2A		no assertion provided	literature only
Natera, Inc.	RCV000176251	SCV002085562	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-12-08	no assertion criteria provided	clinical testing