ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.749A>G (p.Lys250Arg)

gnomAD frequency: 0.00001  dbSNP: rs779939785
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000369442 SCV000344162 uncertain significance not provided 2016-07-27 criteria provided, single submitter clinical testing
Invitae RCV000700400 SCV000829153 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-02-10 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 250 of the CAPN3 protein (p.Lys250Arg). This variant is present in population databases (rs779939785, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 289752). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics RCV001267486 SCV001445667 uncertain significance Inborn genetic diseases 2019-06-18 criteria provided, single submitter clinical testing
3billion RCV000700400 SCV003841412 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.40; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CAPN3 related disorder (PMID: 35169782). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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