Submissions for variant NM_003098.3(SNTA1):c.787G>T (p.Ala263Ser)

gnomAD frequency: 0.00054  dbSNP: rs150576530

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171097	SCV000050728	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000171097	SCV000223662	uncertain significance	not provided	2019-07-10	criteria provided, single submitter	clinical testing	Reported in a male adolescent with lone atrial fibrillation (Husser et al., 2017); Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx; segregation data is limited or absent at this time; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 190914; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28837624, 23861362)
Invitae	RCV000206185	SCV000261464	uncertain significance	Long QT syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 263 of the SNTA1 protein (p.Ala263Ser). This variant is present in population databases (rs150576530, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with atrial fibrillation (PMID: 28837624). ClinVar contains an entry for this variant (Variation ID: 190914). 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	RCV000266318	SCV000433505	uncertain significance	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000678949	SCV000433506	uncertain significance	Long QT syndrome 12	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000185526	SCV000605230	uncertain significance	not specified	2017-03-11	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678949	SCV000805163	uncertain significance	Long QT syndrome 12	2018-04-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408740	SCV002676841	likely benign	Cardiovascular phenotype	2019-05-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000266318	SCV004175715	likely benign	Congenital long QT syndrome	2023-08-08	criteria provided, single submitter	clinical testing	Heterozygous variant NM_003098:c.787G>T (p.Ala263Ser) in the SNTA1 gene was found on WES data in female proband (13 y.o., Caucasian) with Long QT syndrome. An additional variant NM_000238:c.2653C>T (p.Arg885Cys) in the KCNH2 gene was found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0004748 (Date of access 08-08-2023). Clinvar contains entry for this variant (Variation ID: 190914). This variant has been reported in 2 studies in patients with variable phenotypes (PMID: 28837624, 23861362). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria and enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Likely benign with following criteria selected: BS1, BP4.