Submissions for variant NM_000070.3(CAPN3):c.1099G>A (p.Gly367Ser)

gnomAD frequency: 0.00006  dbSNP: rs767106920

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537811	SCV000645461	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 367 of the CAPN3 protein (p.Gly367Ser). This variant is present in population databases (rs767106920, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 25079074, 32403337, 33250842; Invitae). ClinVar contains an entry for this variant (Variation ID: 468639). 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 does not substantially affect CAPN3 function (PMID: 17236769). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000537811	SCV000793690	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282221	SCV002572440	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-08-31	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1099G>A (p.Gly367Ser) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) 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 5.5e-05 in 199358 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.5e-05 vs 0.0032), allowing no conclusion about variant significance. c.1099G>A has been reported in the literature as a biallelic genotype in individuals affected with Limb-Girdle Muscular Dystrophy (Saenz_2005, Milic_2007, Nilsson_2014, Gonzalez-Quereda_2020). These data indicate that the variant is likely to be associated with disease. In vitro analysis of muscle biopsy homogenate from a patient demonstrated normal cleavage activity, however the authors suggest that other functional characteristics may be deficient as they only assayed whole tissue homogenates (Milic_2007). Three ClinVar submitters have assessed the variant since 2014 without evidence for independent evaluation: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002491061	SCV002783014	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2021-11-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003144340	SCV003828949	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476295	SCV004211580	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-27	criteria provided, single submitter	clinical testing
GeneDx	RCV003144340	SCV005332553	uncertain significance	not provided	2024-03-22	criteria provided, single submitter	clinical testing	Identified in the single heterozygous state without a second identified CAPN3 variant in a patient with proximal muscle weakness and myopathy, however, this individual was found to be homozygous for a variant in a different gene that may explain the majority of the phenotype (PMID: 33250842); 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: 34201303, 15689361, 32403337, 17236769, 25079074, 16627476, 33250842)
Natera, Inc.	RCV000537811	SCV002085499	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-11-04	no assertion criteria provided	clinical testing