Submissions for variant NM_000335.5(SCN5A):c.4832T>A (p.Ile1611Asn)

dbSNP: rs1553693063

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000618724	SCV000738068	uncertain significance	Cardiovascular phenotype	2017-06-12	criteria provided, single submitter	clinical testing	The p.I1612N variant (also known as c.4835T>A), located in coding exon 27 of the SCN5A gene, results from a T to A substitution at nucleotide position 4835. The isoleucine at codon 1612 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported in a study of patients referred to an inherited arrhythmia clinic; however, clinical details were limited (Adler A et al. Circ Arrhythm Electrophysiol. 2016;9:e003440). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000786218	SCV000812537	uncertain significance	not provided	2022-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1612 of the SCN5A protein (p.Ile1612Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 519469). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
All of Us Research Program, National Institutes of Health	RCV004802300	SCV005428245	uncertain significance	Cardiac arrhythmia	2024-08-06	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786218	SCV000924949	uncertain significance	not provided	2017-07-11	no assertion criteria provided	provider interpretation	This variant was found in a patient with clinical LQTS who also has a clearly pathogenic KCNQ1 variant: p.Arg518*. p.Ile1612Asn (I1612N; c.4835T>A) in the SCN5A gene (NM_198056) Chromosome position 3:38593028 A/ T Based on the information reviewed below, we classify this as a Variant of Unknown Signficiance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing at this time. It has been reported in one family with LQTS, and is absent from population databases. To determine whether it segregates with LQTS in our proband’s family, we have recommended testing any clearly-affected family members for this variant. This variant has been previously reported in a study of patients referred to an inherited arrhythmia clinic (Adler et al. 2016, Circ Arrhythm Electrophysiol; PMID:26743238). It was present in 2 patients from one family with LQTS. However, there is no clinical data provided for these patients, and their degree of relationship is not known. As of 7/8/2017 the variant had not been reported to ClinVar. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Isoleucine with a polar Asparagine. Isoleucine at this location is absolutely conserved across ~100 vertebrate species for which we have data. According to the Ambry report, in silico analysis with PolyPhen and SIFT predicts the variant to be possibly damaging/deleterious. This variant is absent from the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good sequencing coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.