Submissions for variant NM_000070.3(CAPN3):c.1435A>G (p.Ser479Gly)

gnomAD frequency: 0.00006  dbSNP: rs201736037

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790779	SCV000331499	pathogenic	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000280277	SCV000391015	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-04-28	criteria provided, single submitter	clinical testing	The CAPN3 c.1435A>G (p.Ser479Gly) variant has been reported in five studies and is found in at least nine patients including four compound heterozygotes and four heterozygotes with calpainopathy, and one compound heterozygote with distal myopathy (Richard et al. 1999; Pogue et al. 2001; Groen et al. 2007; Blazquez et al. 2008; Izumi et al. 2015). Reduced and/or absent calpain-3 expression was demonstrated in muscle biopsies in several of these patients. The p.Ser479Gly variant was absent from at least 100 control chromosomes (Richard et al. 1999), and is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant is located in a well-conserved residue that was described as the start of a cluster of variants that can affect the interaction and assembly of calpain-3 protein domains (Jia et al. 2001). Based on the evidence, the p.Ser479Gly variant is classified as likely pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000280277	SCV000645472	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 479 of the CAPN3 protein (p.Ser479Gly). This variant is present in population databases (rs201736037, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 15689361, 18055493, 18563459, 20694146). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92405). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000790779	SCV001753591	likely pathogenic	not provided	2024-06-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18055493, 27055500, 11166169, 20694146, 27066573, 11297944, 30564623, 34426522, 31589614, 34298987, 18563459, 15689361, 10330340, 32896923)
Athena Diagnostics	RCV000790779	SCV001879795	pathogenic	not provided	2021-04-20	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 identified in multiple unrelated individuals with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Revvity Omics, Revvity	RCV000790779	SCV002018076	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271401	SCV002555832	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-06-11	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1435A>G (p.Ser479Gly) 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 5.6e-05 in 251424 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.1435A>G has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive, specifically Limb-girdle muscular dystrophy type 2A (LGMD2A) (example, Richard_1999, Saenz_2005, Groen_2007, Blazquez_2008, de Morree_2010, Izumi_2015, Toral-Ojeda_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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.
Fulgent Genetics, Fulgent Genetics	RCV002498373	SCV002810972	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2022-03-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474672	SCV004211561	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000280277	SCV000791545	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-05-12	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732653	SCV005344604	pathogenic	CAPN3-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The CAPN3 c.1435A>G variant is predicted to result in the amino acid substitution p.Ser479Gly. This variant has been widely reported in individuals with autosomal recessive muscular dystrophy (see for example, Richard et al. 1999. PubMed ID: 10330340; González-Mera et al. 2020. PubMed ID: 32896923; Groen et al. 2007. PubMed ID: 18055493). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.