ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2338G>C (p.Asp780His) (rs778768583)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Limb-girdle muscular dystrophy, type 2A 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 780 of the CAPN3 protein (p.Asp780His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs778768583, ExAC 0.006%). This variant has been reported as homozygous and/or in combination with another CAPN3 variant in many individuals affected with limb-girdle muscular dystrophy. It has been described as a founder mutation in the Agarwal community originating from northern India (PMID: 15733273, 25079074, 27011640, 23666804). Experimental studies have shown that this missense change results in reduced protein expression and autolytic activity in muscle biopsy samples (PMID: 25079074). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000176251 SCV001164527 pathogenic 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).
Counsyl RCV000176251 SCV000789634 likely pathogenic 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 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.

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