ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1535C>T (p.Thr512Ile)

dbSNP: rs199473118
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000588264 SCV000291778 uncertain significance not provided 2023-05-26 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects SCN5A function (PMID: 12569159). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 67665). This missense change has been observed in individual(s) with atrioventricular (AV) conduction block and cardiomyopathy (PMID: 12569159, 27554632). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 512 of the SCN5A protein (p.Thr512Ile).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Fulgent Genetics, Fulgent Genetics RCV002498340 SCV002814071 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2022-02-24 criteria provided, single submitter clinical testing
GeneDx RCV000588264 SCV004039685 uncertain significance not provided 2023-09-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in patients with arrhythmia and cardiomyopathy and in an unaffected relative (Viswanathan et al., 2003; Priganc et al., 2016); This variant is associated with the following publications: (PMID: 12569159, 27554632, 29728395)
All of Us Research Program, National Institutes of Health RCV003996525 SCV004831241 uncertain significance Cardiac arrhythmia 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 512 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A functional study has suggested that this variant may affect sodium channel function (PMID: 12569159). This variant has been reported in an individual affected with atrioventricular block (PMID: 12569159), as well as in an individual affected with dilated cardiomyopathy and an individual affected with hypertrophic cardiomyopathy (PMID: 27554632). This variant has been identified in 1/229040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000058426 SCV000089946 not provided Conduction system disorder 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 not provided Brugada syndrome 1 no assertion provided literature only
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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