Submissions for variant NM_003098.3(SNTA1):c.759T>A (p.Asp253Glu)

gnomAD frequency: 0.00001  dbSNP: rs759487225

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171095	SCV000223660	uncertain significance	not provided	2017-08-29	criteria provided, single submitter	clinical testing	The D253E variant of uncertain significance in the SNTA1 gene has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been observed in other unrelated individuals referred for cardiac genetic testing at GeneDx. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the D253E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, the D253E variant was observed in 6/63,534 alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) (Lek et al., 2016).
Invitae	RCV001852057	SCV002234519	uncertain significance	Long QT syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 253 of the SNTA1 protein (p.Asp253Glu). This variant is present in population databases (rs759487225, gnomAD 0.01%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 190912). This variant has not been reported in the literature in individuals affected with SNTA1-related conditions.
Ambry Genetics	RCV002390407	SCV002675248	uncertain significance	Cardiovascular phenotype	2019-04-09	criteria provided, single submitter	clinical testing	The p.D253E variant (also known as c.759T>A), located in coding exon 4 of the SNTA1 gene, results from a T to A substitution at nucleotide position 759. The aspartic acid at codon 253 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485080	SCV002793681	uncertain significance	Long QT syndrome 12	2021-07-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387785	SCV004100149	uncertain significance	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: SNTA1 c.759T>A (p.Asp253Glu) results in a conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250780 control chromosomes. The observed variant frequency is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Long QT Syndrome phenotype (3.3e-06), suggesting that the variant is benign, although penetrance is reduced and symptoms may present in adulthood. c.759T>A has been reported in the literature in one individual with clinical features of long QT syndrome (Gibbs_2018). This individual had an additional variant in the CACNA1C gene, and the authors classified both alterations as uncertain significance. Therefore, this report does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30369311). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.