ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1715G>A (p.Arg572Gln) (rs121434544)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000019180 SCV000255657 pathogenic Limb-girdle muscular dystrophy, type 2A 2015-08-18 criteria provided, single submitter clinical testing
Invitae RCV000019180 SCV000645479 pathogenic Limb-girdle muscular dystrophy, type 2A 2019-05-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 572 of the CAPN3 protein (p.Arg572Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121434544, ExAC 0.006%). This variant has been reported in the homozygous and compound heterozygous states in individuals affected with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) (PMID: 7720071, 10102422, 27066545, 27708273, 16650086). ClinVar contains an entry for this variant (Variation ID: 17614). Experimental studies have shown that this missense change severely reduced autolytic activity and Ca2+ dependent autolysis (PMID: 9642272, 16627476). A different missense substitution at this codon (p.R472W) has been determined to be pathogenic (PMID: 9150160, 16650086, 10330340, 15221789). This suggests that the arginine residue is critical for CAPN3 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726518 SCV000701547 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198825 SCV001369820 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2020-03-24 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PP3,PP4.
GeneDx RCV000726518 SCV001767321 pathogenic not provided 2021-01-11 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant reduces autolytic activity (Ono et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 7720071, 32528171, 27708273, 31589614, 10094566, 19156839, 27500519, 10639725, 31410652, 16627476, 9642272, 10102422, 10330340, 15221789, 16650086, 27066545, 10818750, 8624690)
OMIM RCV000019180 SCV000039468 pathogenic Limb-girdle muscular dystrophy, type 2A 1995-04-07 no assertion criteria provided literature only
Counsyl RCV000019180 SCV000796548 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2017-12-27 no assertion criteria provided clinical testing

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