Submissions for variant NM_000719.7(CACNA1C):c.1753G>A (p.Val585Met)

gnomAD frequency: 0.00010  dbSNP: rs763738559

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617554	SCV000737595	likely benign	Cardiovascular phenotype	2022-04-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000631714	SCV000752801	uncertain significance	Long QT syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 585 of the CACNA1C protein (p.Val585Met). This variant is present in population databases (rs763738559, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 519274). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. 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.
GeneDx	RCV001591382	SCV001823820	uncertain significance	not provided	2020-09-30	criteria provided, single submitter	clinical testing	Has been reported in an individual with sudden unexplained death at 36 years of age, and cardiac findings on autopsy showed interstitial fibrosis and myocyte hypertrophy (Shanks et al., 2018); however, a frameshift variant in the A-band of the TTN gene was also identified and no family history or segregation details were reported.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29915097)
Fulgent Genetics, Fulgent Genetics	RCV002483715	SCV002791278	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-08-18	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001591382	SCV001921611	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001591382	SCV001971340	uncertain significance	not provided		no assertion criteria provided	clinical testing