ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5975G>T (p.Cys1992Phe)

gnomAD frequency: 0.00024  dbSNP: rs375818733
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000475281 SCV000553024 likely benign Long QT syndrome 2023-12-11 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000622425 SCV000740555 uncertain significance Brugada syndrome 2017-05-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001812147 SCV001471496 uncertain significance not provided 2020-06-23 criteria provided, single submitter clinical testing The CACNA1C c.5975G>T; p.Cys1992Phe variant (rs375818733) is reported in the literature in an individual affected with ventricular fibrillation, but without a clear association with disease (Blancard 2018). This variant is reported in ClinVar (Variation ID: 190628), and is found in the general population with an overall allele frequency of 0.011% (30/279868 alleles) in the Genome Aggregation Database. The cysteine at codon 1992 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Functional analyses of the variant protein show no significant difference compared to wild type (Blancard 2018). However, due to limited information, the clinical significance of the p.Cys1992Phe variant is uncertain at this time. References: Blancard M et al. An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation. Sci Rep. 2018;8(1):14619.
Ambry Genetics RCV002354418 SCV002658368 benign Cardiovascular phenotype 2022-09-09 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV002478532 SCV002782663 uncertain significance Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8 2021-11-22 criteria provided, single submitter clinical testing

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