ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1535C>T (p.Thr512Ile) (rs199473118)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058426 SCV000089946 not provided Cardiac conduction defect, nonspecific no assertion provided literature only This variant has been reported as associated with Cardiac conduction disease in the following publications (PMID:12569159). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneReviews RCV000144029 SCV000188922 pathogenic Brugada syndrome 1 2014-04-10 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000588264 SCV000700018 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.1535C>T (p.Thr512Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/67122 control chromosomes at a frequency of 0.0000149, which does not exceed the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001). This variant was identified in at least one pt with cardiac conduction disease without strong segregation due to possibly reduced penetrance and in 2 patients with DCM/HCM. Functional study showed that the variant caused abnormal gating effects. GeneReviews cites this variant as pathogenic, although other clinical diagnostic laboratories classify the variant as VUS. Taking together, the variant is classified as VUS-Possibly Pathogenic.
Invitae RCV000234724 SCV000291778 uncertain significance Brugada syndrome 2016-03-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 512 of the SCN5A protein (p.Thr512Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs199473118, ExAC <0.01%). This variant has been reported in an individual affected with atrioventricular (AV) conduction block (PMID: 12569159). ClinVar contains an entry for this variant (Variation ID: 9398, 67665). One experimental study has shown that this missense change causes hyperpolarizing shifts in activation and inactivation, as well as slow inactivation (PMID: 12569159). In summary, this variant is a rare missense change that has been reported in one individual affected with AV conduction block and shown to affect protein function. However in the absence of additional genetic and functional data at this point this variant has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000588264 SCV000924956 uncertain significance not provided 2016-04-22 no assertion criteria provided provider interpretation The variant has been reported in one 2-year-old individual with second-degree atrioventricular (AV) block (Viswanathan 2003). Functional expression studies showed that voltage-dependent activation and inactivation had enhanced slow activation and slow recovery from inactivation when compared to wildtype (OMIM 600163.0031; Viswanathan 2003).

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