Submissions for variant NM_003098.3(SNTA1):c.566C>T (p.Ser189Leu)

gnomAD frequency: 0.00020  dbSNP: rs144860423

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251711	SCV000318682	likely benign	Cardiovascular phenotype	2022-03-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587989	SCV000698166	likely benign	not provided	2016-04-26	criteria provided, single submitter	clinical testing	Variant summary: The c.566C>T in SNTA1 gene is a missense change that alters a highly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.02%, predominantly in individuals of European descent (0.03%). These frequencies exceed the maximal expected allele frequency for a pathogenic variant in SNTA1 gene (0.001%). The variant of interest has not, to our knowledge, been reported in affected individuals in published reports or cited by a reputable database/diagnostic center. Taking together, the variant was classified as Likely Benign.
Illumina Laboratory Services, Illumina	RCV000624991	SCV001303915	uncertain significance	Long QT syndrome 12	2018-03-30	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.
Invitae	RCV001213908	SCV001385564	uncertain significance	Long QT syndrome	2023-12-24	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 189 of the SNTA1 protein (p.Ser189Leu). This variant is present in population databases (rs144860423, gnomAD 0.04%). This missense change has been observed in individual(s) with atrial fibrillation, arrhythmogenic right ventricular cardiomyopathy, sudden infant death syndrome, and sudden cardiac arrest (PMID: 28074886, 28837624, 30847666, 30975432). ClinVar contains an entry for this variant (Variation ID: 263623). 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.
GeneDx	RCV000587989	SCV001771674	uncertain significance	not provided	2021-01-04	criteria provided, single submitter	clinical testing	Variant has been reported in the literature in patients with lone atrial fibrillation, unspecified arrhythmia, ARVC, and/or sudden cardiac death, most of whom also harbored additional cardiac variants thought to contribute to disease (Husser et al., 2017; Proost et al., 2017, van Lint et al., 2019); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #263623; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 28837624, 28341588)