ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.689T>C (p.Ile230Thr) (rs199473073)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000527599 SCV000637203 uncertain significance Brugada syndrome 2020-01-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 230 of the SCN5A protein (p.Ile230Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with sinus node syndrome in a recessive fashion in a family (PMID: 20564468). ClinVar contains an entry for this variant (Variation ID: 68036). Experimental studies have shown that this missense change results in a positive shift in channel activation, along with a negative shift in inactivation compared to wild-type (PMID: 20564468). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001187126 SCV000700044 likely pathogenic Arrhythmia 2021-05-21 criteria provided, single submitter clinical testing Variant summary: SCN5A c.689T>C (p.Ile230Thr) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 237066 control chromosomes (gnomAD). c.689T>C has been reported in the literature in a large white Russian pedigree where four siblings (from third generation) were homozygous for the variant and presented with sinus bradycardia with a first-degree AV block and significantly prolonged age-corrected QRS intervals. Multiple additional family members were genotyped and were found to be asymptomatic heterozygous carriers, therefore, suggesting that the phenotype is caused by recessive mode of inheritance (Neu_2010). The authors of this report also performed functional studies in stable cell lines over-expressing the wild type and the mutant SCN5A and reported that the variant of interest had "normal protein transport but altered biophysical sodium channel properties. Voltage range of both activation and inactivation were shifted in a way that resulted in decreased sodium current and loss of channel function." A recent functional study, using induced pluripotent stem cells derived cardiomyocytes isolated from the homozygous patients and heterozygous carriers described by Neu_2010, also reported a markedly reduced sodium current in homozygous cells, whereas heterozygous cells displayed an intermediate reduction (Veerman_2017). Two other ClinVar submitters (evaluation after 2014) cite the variant uncertain significance. Therefore, due to the findings being based solely on this one family along with the fact that other potential cardiac genes were not screened, the variant of interest has been classified as likely pathogenic for recessive mode of inheritance.
Color Health, Inc RCV001187126 SCV001353811 uncertain significance Arrhythmia 2019-05-28 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058839 SCV000090359 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:20564468). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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