Submissions for variant NM_003098.3(SNTA1):c.1442C>T (p.Ser481Leu)

gnomAD frequency: 0.00007  dbSNP: rs370531842

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168024	SCV000218676	uncertain significance	Long QT syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 481 of the SNTA1 protein (p.Ser481Leu). This variant is present in population databases (rs370531842, gnomAD 0.008%). This missense change has been observed in individual(s) with sudden cardiac arrest (PMID: 30403391). ClinVar contains an entry for this variant (Variation ID: 188145). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SNTA1 protein function with a negative predictive value of 80%. 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.
Illumina Laboratory Services, Illumina	RCV001136715	SCV001296574	uncertain significance	Long QT syndrome 12	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527060	SCV001737896	likely benign	not specified	2021-06-13	criteria provided, single submitter	clinical testing	Variant summary: SNTA1 c.1442C>T (p.Ser481Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 282818 control chromosomes. The observed variant frequency is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. c.1442C>T has been reported in the literature in individuals affected with sudden cardiac death (example, PMID 30403391). These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory ( KCNQ1 c.1702G>A , p.Gly568Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002390400	SCV002700225	uncertain significance	Cardiovascular phenotype	2021-12-23	criteria provided, single submitter	clinical testing	The p.S481L variant (also known as c.1442C>T), located in coding exon 8 of the SNTA1 gene, results from a C to T substitution at nucleotide position 1442. The serine at codon 481 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.