Submissions for variant NM_000070.3(CAPN3):c.1333G>A (p.Gly445Arg)

dbSNP: rs773827877

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725472	SCV000337170	pathogenic	not provided	2017-03-28	criteria provided, single submitter	clinical testing
Invitae	RCV000405059	SCV000953639	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 445 of the CAPN3 protein (p.Gly445Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 10330340, 15221789, 17236769, 18854869; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 284515). 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) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 15221789, 17236769, 20635405). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000405059	SCV001164533	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Gly445Arg variant in CAPN3 was identified by our study in two unrelated individuals in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006295% (4/63542) of European (non-Finnish) chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773827877). 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. There are several individuals in the literature with LGMD and this variant in either the compound heterozygous state or with no other known causative variant (PMID: 17994539). In summary, although additional studies are required to fully establish its clinical significance, the clinical significance of the p.Gly445Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_Strong, PP3 (Richards 2015).
Revvity Omics, Revvity	RCV000725472	SCV002018063	pathogenic	not provided	2023-07-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282104	SCV002571894	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-08-09	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1333G>A (p.Gly445Arg) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 240268 control chromosomes. c.1333G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, with recent reports associating this variant with an autosomal dominant mode of inheritance (example, Saenz_2005, Avila_2015, Guglieri_2008, Aguennouz_2016, Cerino_2020, Macias_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating that the variant impacts calpain-3 catalytic activity and intra/intermolecular autolysis (Cerino_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000725472	SCV004033373	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	CAPN3: PP1:Strong, PS1, PM1, PP3, PS3:Supporting
Baylor Genetics	RCV003475905	SCV004211553	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-10-02	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000725472	SCV004229510	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been seen in multiple individuals with apparently autosomal recessive LGMD (PMID: 10330340, 17994539, 20635405). It has also been reported to segregate with autosomal dominant LGMD in several families (PMID: 32342993). Experiments in patient-derived samples showed absence or significant reduction in CAPN3 protein level/activity in multiple patients.
Counsyl	RCV000405059	SCV000791979	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-06-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000405059	SCV001454340	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-16	no assertion criteria provided	clinical testing