Submissions for variant NM_003098.3(SNTA1):c.992G>A (p.Arg331His)

gnomAD frequency: 0.00004  dbSNP: rs575431717

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171100	SCV000223665	uncertain significance	not provided	2014-06-18	criteria provided, single submitter	clinical testing	The R331H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R331H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the R331H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with LQTS or arrhythmia, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae	RCV000559623	SCV000627705	uncertain significance	Long QT syndrome	2023-06-15	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: 190917). This variant has not been reported in the literature in individuals affected with SNTA1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 331 of the SNTA1 protein (p.Arg331His).
Illumina Laboratory Services, Illumina	RCV001138963	SCV001299058	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.
Ambry Genetics	RCV002381547	SCV002694358	uncertain significance	Cardiovascular phenotype	2021-03-23	criteria provided, single submitter	clinical testing	The p.R331H variant (also known as c.992G>A), located in coding exon 5 of the SNTA1 gene, results from a G to A substitution at nucleotide position 992. The arginine at codon 331 is replaced by histidine, an amino acid with highly similar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV001138963	SCV002788413	uncertain significance	Long QT syndrome 12	2021-10-21	criteria provided, single submitter	clinical testing