Submissions for variant NM_000070.3(CAPN3):c.1257T>G (p.Asp419Glu)

gnomAD frequency: 0.00001  dbSNP: rs139836397

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	RCV004999209	SCV005620245	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2025-01-09	reviewed by expert panel	curation	The NM_000070.3: c.1257T>G variant in CAPN3 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 419 (p.Asp419Glu). This variant has been detected in at least ten unrelated individuals with LGMD (PMID: 18055493, 25079074, 30564623; LOVD CAPN3_000280; ClinVar SCV000953543.3 internal data communication, ClinVar SCV002025057.3 internal data communication, ClinVar SCV001879783.1 internal data communication), including in unknown phase with a pathogenic variant in six cases (c.550delA p.(Thr184ArgfsTer36), 1.0 pt, PMID: 18055493, SCV002025057.3; c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1027G>T p.(Glu343Ter), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1838del p.(Lys613ArgfsTer49), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.643_663del p.(Ser215_Gly221del), 0.5 pts, ClinVar SCV001879783.1 internal data communication) (PM3_Strong). In four individuals, a second variant in CAPN3 was not identified. At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID: 18055493) (PP4). The filtering allele frequency of this variant is 0.00006819 (the upper threshold of the 95% CI of 3/113704 European (non-Finnish) exome alleles) by gnomAD v2.1.1, which is less than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Strong, PP4, PM2_Supporting, PP3.
Eurofins Ntd Llc (ga)	RCV000342508	SCV000334587	likely pathogenic	not provided	2018-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813198	SCV000953543	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 419 of the CAPN3 protein (p.Asp419Glu). This variant is present in population databases (rs139836397, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 18055493, 25079074). ClinVar contains an entry for this variant (Variation ID: 282873). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics	RCV000342508	SCV001879783	uncertain significance	not provided	2020-11-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000342508	SCV002025057	likely pathogenic	not provided	2019-06-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475898	SCV004211552	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732819	SCV005354979	likely pathogenic	CAPN3-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The CAPN3 c.1257T>G variant is predicted to result in the amino acid substitution p.Asp419Glu. This variant was reported along with a second early termination change (phase not specified) in two brothers with limb-girdle muscular dystrophy (LGMD), and functional studies support its pathogenicity (Groen et al. 2007. PubMed ID: 18055493; Garnham et al. 2009. PubMed ID: 19226146). It has also been reported in the heterozygous state in one carrier and one affected individual in whom no second CAPN3 variant was detected (Capalbo et al. 2019. PubMed ID: 31589614; Nilsson et al. 2014. PubMed ID: 25079074). A different amino acid change at same position (p.Asp419Gly) has also been reported along with a second CAPN3 variant in patient with LGMD (Groen et al. 2007. PubMed ID: 18055493). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.