ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2813T>C (p.Ile938Thr) (rs377165829)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486236 SCV000565758 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TMEM43 gene. Haywood et al. (2013) observed theE124K variant in two unrelated individuals with ARVC who had a family history of ARVC/DCM, however, theyalso observed this variant in a homozygous state in a control individual. Segregation analysis of E124K with diseasein these families was not completed (Haywood et al., 2013). The E124K variant was also reported in a 47-year-oldfemale with minimal symptoms and no family history of ARVC, who also harbored a DSP variant of uncertainsignificance (Baskin et al., 2013). The NHLBI Exome Sequencing Project and the 1000 Genomes Project reportE124K was observed in 13/8600 (0.2%) alleles from individuals of European background and in 3/694 (0.4%) allelesfrom individuals of Ad Mixed American background, indicating it may be a rare benign variant in these populations.However, the E124K variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs ata position that is conserved across species. Nonetheless, in silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000797310 SCV000936859 uncertain significance Long QT syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 938 of the CACNA1C protein (p.Ile938Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs377165829, ExAC 0.01%). This variant has not been reported in the literature in individuals with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 308140). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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