Submissions for variant NM_000335.5(SCN5A):c.689T>C (p.Ile230Thr)

gnomAD frequency: 0.00001  dbSNP: rs199473073

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654195	SCV000637203	pathogenic	not provided	2024-03-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 230 of the SCN5A protein (p.Ile230Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive sinus node syndrome (PMID: 20564468). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68036). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 20564468). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001842409	SCV000700044	likely pathogenic	Cardiac 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 Diagnostics, LLC DBA Color Health	RCV001842409	SCV001353811	uncertain significance	Cardiac arrhythmia	2023-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 230 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region (a.a.132-410) in transmembrane domain DI. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a reduction of sodium current and a shift in the voltage-dependence of activation and inactivation (PMID: 20564468, 28739862). This variant has been reported in homozygosity in four siblings affected with cardiac conduction disease (PMID: 20564468). Their heterozygous parents and 9 other heterozygous carriers in this family were asymptomatic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although one study suggests that this variant may be associated with autosomal recessive cardiac conduction disease, the available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmia or Brugada syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001842409	SCV004841117	uncertain significance	Cardiac arrhythmia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 230 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region (a.a.132-410) in transmembrane domain DI. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a reduction of sodium current and a shift in the voltage-dependence of activation and inactivation (PMID: 20564468, 28739862). This variant has been reported in homozygosity in four siblings affected with cardiac conduction disease (PMID: 20564468). Their heterozygous parents and 9 other heterozygous carriers in this family were asymptomatic. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although one study suggests that this variant may be associated with autosomal recessive cardiac conduction disease, the available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmia or Brugada syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058839	SCV000090359	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:20564468). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.