ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.689T>C (p.Ile230Thr) (rs199473073)

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Total submissions: 3
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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 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.
Integrated Genetics/Laboratory Corporation of America RCV000588942 SCV000700044 likely pathogenic Long QT syndrome 1 2017-05-01 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.689T>C (p.Ile230Thr) variant located in the fourth transmembrane domain known to be involved in voltage-dependent gating of sodium channels (via Neu_2010) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGo not captured here due to low reliability index) predict a damaging outcome. The variant of interest was not observed in 57476 control chromosomes (ExAC and publication controls). A publication, Neu_2010, cites the variant in a large White Russia pedigree, where the four siblings (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 a homozygous or compound heterozygous mode of inheritance. In addition, the authors, Neu_2010, performed functional studies on the variant, which revealed "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." The variant of interest has not been reported by clinical diagnostic laboratories. Therefore, due to the findings being based solely on this one family and study, along with the fact that other potential cardiac genes were not screened, the variant of interest has been classified as "likely pathogenic."
Invitae RCV000527599 SCV000637203 uncertain significance Brugada syndrome 2018-09-24 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.

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