ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2092C>T (p.Arg698Cys)

gnomAD frequency: 0.00001  dbSNP: rs764370512
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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) RCV000327815 SCV000338651 uncertain significance not provided 2016-01-22 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000675154 SCV001164499 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-12-03 criteria provided, single submitter research The homozygous p.Arg698Cys variant in CAPN3 was identified by our study in two unrelated individuals with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.002689% (3/111558) of European (non-Finnish) chromosomes and 0.002978% (1/33582) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764370512). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg698Cys variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).
Invitae RCV000675154 SCV001376109 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 698 of the CAPN3 protein (p.Arg698Cys). This variant is present in population databases (rs764370512, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 16650086, 21204801, 28403181). ClinVar contains an entry for this variant (Variation ID: 285572). 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%. This variant disrupts the p.Arg698 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 16411092, 25135358), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000327815 SCV002018043 pathogenic not provided 2020-01-03 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000675154 SCV002600905 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-10-14 criteria provided, single submitter clinical testing A homozygous variation in exon 19 of the CAPN3 gene that results in the amino acid substitution cysteine for arginine at codon 698 was detected. The observed variant reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT and MutationTaster2. The reference codon is conserved across species.
Illumina Laboratory Services, Illumina RCV000675154 SCV004014844 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-03-07 criteria provided, single submitter clinical testing The CAPN3 c.2092C>T (p.Arg698Cys) missense variant results in the substitution of arginine at amino acid position 698 with cysteine. This variant has been reported in the literature in at least six individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD), including in a homozygous state in one individual and in a compound heterozygous state in five individuals (PMID: 16650086; PMID: 17236769; PMID: 21204801; PMID: 28403181; PMID: 33250842; PMID: 35169782). Additionally, two different amino acid substitutions at the same codon (Arg698His, Arg698Pro) have been reported in individuals with LGMD (PMID: 25135358; PMID: 10330340). This variant is reported in the Genome Aggregation Database at a frequency of 0.000029 in the Latino/Admixed American population (version 2.1.1). The c.2092C>T variant is located within EF-hand 2 domain, which has a low rate of benign variation (UniProt:P20807; PMID: 35169782). Based on the available evidence, the c.2092C>T (p.Arg698Cys) variant is classified as pathogenic for limb-girdle muscular dystrophy.
Baylor Genetics RCV003463760 SCV004213778 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-04-29 criteria provided, single submitter clinical testing
Counsyl RCV000675154 SCV000800764 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-05-10 no assertion criteria provided clinical testing

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