Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000183185 | SCV000235602 | uncertain significance | not provided | 2011-11-28 | criteria provided, single submitter | clinical testing | p.Val1237Ile in the SCN5A gene; variant of unknown clinical significance. The G>A nucleotide substitution in exon 21 of the SCN5A gene, results in replacement of the normal Valine codon (GTT) with an Isoleucine codon (ATT) at amino acid position 1237 in the cardiac sodium voltage-gated channel, type V-a. This missense change is denoted Val1237Ile (aka V1237I) at the protein level and c.3709 G>A at the cDNA level. The Val1237Ile variant in the SCN5A gene has not been published as a disease-causing mutation or as a benign polymorphism, to our knowledge. The Val1237Ile variant results in a conservative amino acid substitution of one non-polar amino acid for another, at a position that is not conserved in other species or in other related proteins. In addition, in-silico analysis predicts Val1237Ile to be benign (Adzhubei IA et a. 2010, Kumar P et al. 2009, Schwarz JM et al. 2010). However, mutations in surrounding codons (Arg1232Trp, Lys1236Asn, Glu1240Gln) have been reported in association with arrhythmia supporting the functional importance of this region of the protein. Finally, Val1237Ile was not observed in up to 200 African American control alleles tested at GeneDx, indicating it is not a benign polymorphism in this population. With the clinical and molecular information available at this time, we cannot unequivocally determine the clinical significance of Val1237Ile in the SCN5A gene. The variant is found in LQT panel(s). |
| All of Us Research Program, |
RCV003996822 | SCV004824720 | uncertain significance | Cardiac arrhythmia | 2023-05-04 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 1237 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has not been identified 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. |