Submissions for variant NM_000070.3(CAPN3):c.2093G>A (p.Arg698His)

gnomAD frequency: 0.00004  dbSNP: rs190793093

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597401	SCV000704334	uncertain significance	not provided	2017-01-23	criteria provided, single submitter	clinical testing
Invitae	RCV000644983	SCV000766713	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2022-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 698 of the CAPN3 protein (p.Arg698His). This variant is present in population databases (rs190793093, gnomAD 0.01%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (LGMD) type 2A (PMID: 25135358, 30564623). ClinVar contains an entry for this variant (Variation ID: 499036). 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 not expected to disrupt CAPN3 protein function. This variant disrupts the p.Arg698 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330340, 15689361, 16411092, 21204801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000644983	SCV000778587	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-04-16	criteria provided, single submitter	research
Counsyl	RCV000644983	SCV000790334	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476300	SCV002784907	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2022-04-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000597401	SCV003828994	uncertain significance	not provided	2020-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387895	SCV004099913	uncertain significance	not specified	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.2093G>A (p.Arg698His) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. This alters a highly conserved amino acid in which other missense changes have been found in association with disease (HGMD), suggesting this may be a clinically important residue. 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 2.4e-05 in 251334 control chromosomes (gnomAD). c.2093G>A has been reported in the literature in two individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Stehlikova_2014, Nallamilli_2018), and one was reported as compound heterozygous with a pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25135358, 30564623). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003459469	SCV004213737	uncertain significance	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-08-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000644983	SCV001456369	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-16	no assertion criteria provided	clinical testing