ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.3679G>A (p.Val1227Ile) (rs373124557)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725545 SCV000337633 uncertain significance not provided 2015-12-07 criteria provided, single submitter clinical testing
Invitae RCV000463570 SCV000553002 uncertain significance Long QT syndrome 2019-02-21 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1227 of the CACNA1C protein (p.Val1227Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs373124557, ExAC 0.01%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 234984). 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 isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV000618584 SCV000737427 uncertain significance Cardiovascular phenotype 2019-08-26 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000763834 SCV000894756 uncertain significance Timothy syndrome; Brugada syndrome 3 2018-10-31 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223923 SCV000280057 uncertain significance not specified 2012-03-18 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed we consider this a variant of uncertain significance. This is a novel variant. It is not reported in dbSNP as a benign polymorphism nor is it reported in published literature in association with disease. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Leucine. Valine is not conserved at this position across species and there are no reported disease associated variants at nearby codons (Google, Gene Connection for the Heart Database, Mutadatabase). In silico analysis (PolyPhen) predicts the amino acid change to be benign. The reporting lab did not find this variant in 600 presumably healthy controls consisting of both Caucasian and African American ancestry.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415626 SCV000493714 uncertain significance Short QT Syndrome 4 2015-07-24 no assertion criteria provided clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000656705 SCV000747830 uncertain significance Timothy syndrome 2017-12-01 no assertion criteria provided clinical testing The observed variant c.3679G>A (p.V1227I) is not reported in 1000 Genomes and has minor allele frequency of 0.00002479 in ExAC database. The in silico prediction of the variant is benign by MutationTaster2 and tolerated by SIFT.

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