ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.640G>A (p.Gly214Ser)

gnomAD frequency: 0.00004  dbSNP: rs369784333
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000597389 SCV000700630 likely pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000597389 SCV001500662 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Invitae RCV000673077 SCV001581101 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-01-29 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 214 of the CAPN3 protein (p.Gly214Ser). This variant is present in population databases (rs369784333, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 19556129, 25135358, 30919934). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 496915). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000597389 SCV001817263 uncertain significance not provided 2020-06-25 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10330340, 30919934, 31589614, 19556129, 25135358, 30564623)
Revvity Omics, Revvity Omics RCV000597389 SCV002016920 pathogenic not provided 2021-06-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509457 SCV002819558 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2022-12-15 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.640G>A (p.Gly214Ser) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251464 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (8.7e-05 vs 0.0032), allowing no conclusion about variant significance. c.640G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/likely pathogenic n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003471951 SCV004211539 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-10-08 criteria provided, single submitter clinical testing
Counsyl RCV000673077 SCV000798245 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-03-08 no assertion criteria provided clinical testing

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