ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1505T>C (p.Ile502Thr) (rs148044781)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414202 SCV000334022 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing
GeneDx RCV000414202 SCV000491158 likely pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing The I502T variant in the CAPN3 gene has been reported previously in association with LGMD2A (Richard et al., 1999). This variant was also reported as a heterozygous variant in one possible LGMD2A patient; although a second CAPN3 variant was not identified in this individual, western blot analysis demonstrated highly reduced CAPN3 protein (Luo et al., 2012). This variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I502T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (I502S) has been reported in the Human Gene Mutation Database in association with LGMD2A (Stenson et al., 2014), supporting the functional importance of this residue of the protein. The I502T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Athena Diagnostics Inc RCV000414202 SCV000612634 likely pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene.
Invitae RCV000644997 SCV000766735 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 502 of the CAPN3 protein (p.Ile502Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs148044781, ExAC 0.03%). This variant has been observed in individual(s) with CAPN3-related conditions (PMID: 10330340, 26810512, 30919934, 22926650, 30564623, Invitae). ClinVar contains an entry for this variant (Variation ID: 282512). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Ile502 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 18337726), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000644997 SCV000800676 uncertain significance Limb-girdle muscular dystrophy, type 2A 2018-03-20 criteria provided, single submitter clinical testing

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