ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys) (rs786205748)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170780 SCV000223335 pathogenic not provided 2019-03-14 criteria provided, single submitter clinical testing Described in another individual with LQTS and a positive family history, though segregation data was not provided (Seo et al., 2018); Reported in ClinVar as pathogenic (ClinVar Variant ID# 190642; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Whole cell patch clamp studies revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current (Boczek et al., 2015); This variant is associated with the following publications: (PMID: 27390944, 26253506, 30513141, 29071820, 30172029, 30345660, 31430211, 32161207)
Invitae RCV000232889 SCV000285587 pathogenic Long QT syndrome 2020-06-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 518 of the CACNA1C protein (p.Arg518Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). However, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. ClinVar contains an entry for this variant (Variation ID: 190642). This variant has been reported to segregate with the disease in three families affected with long QT syndrome (LQTS), hypertrophic cardiomyopathy (HCM) and septal defects (CHD) (PMID: 26253506, Invitae). Experimental studies have shown that this variant decreases the voltage-dependent inactivation of the channel (PMID: 26253506). In summary, this variant has been found to segregate with the disease in three affected families and leads to a gain of function of the channel. For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000170780 SCV000924764 likely pathogenic not provided 2016-04-14 no assertion criteria provided provider interpretation

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