Submissions for variant NM_003098.3(SNTA1):c.430T>G (p.Ser144Ala)

gnomAD frequency: 0.00017  dbSNP: rs142978180

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489834	SCV000577193	uncertain significance	not provided	2017-04-07	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SNTA1 gene. The S144A variant has been previously reported in one case of sudden infant death syndrome (SIDS) (Brion et al., 2014); however, this infant also harbored an additional missense variant in the KCNE1 gene and no further clinical details or segregation studies were described. The S144A variant has also been observed in 8/10406 (0.08%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S144A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics	RCV000620309	SCV000736440	likely benign	Cardiovascular phenotype	2022-12-30	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.
Invitae	RCV001346075	SCV001540245	uncertain significance	Long QT syndrome	2023-09-01	criteria provided, single submitter	clinical testing	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: 426680). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 24981977). This variant is present in population databases (rs142978180, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 144 of the SNTA1 protein (p.Ser144Ala).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000489834	SCV001554333	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SNTA1 p.S144A variant was not identified in the literature but was identified in dbSNP (ID: rs142978180) and ClinVar (classified as uncertain significance by GeneDx and Ambry Genetics). The variant was identified in control databases in 15 of 282886 chromosomes at a frequency of 0.00005302, and was observed only in the African population in 15 of 24970 chromosomes (freq: 0.0006007) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.S144 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.