Submissions for variant NM_003098.3(SNTA1):c.160G>C (p.Gly54Arg)

gnomAD frequency: 0.00003  dbSNP: rs786205848

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171117	SCV000223682	uncertain significance	not provided	2018-04-19	criteria provided, single submitter	clinical testing	The G54R variant of uncertain significance in the SNTA1 gene was previously reported in one SIDS case (Cheng et al., 2009). This variant has also been identified in multiple unrelated individuals referred for cardiac genetic testing at GeneDx. However, two individuals also harbor pathogenic or likely pathogenic variants in other genes that likely explain their disease phenotype, and currently available segregation data is non-informative. The G54R variant is observed in 4/1,850 alleles from individuals of Latino ancestry and 5/24,724 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). G54R 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, functional studies determined the G54R variant is equivalent to the wildtype; showing functionally insignificant changes in the sodium current (Cheng et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000705669	SCV000834678	uncertain significance	Long QT syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 54 of the SNTA1 protein (p.Gly54Arg). This variant is present in population databases (rs786205848, gnomAD 0.04%). This missense change has been observed in individual(s) with Long QT Syndrome and/or sudden infant death syndrome (PMID: 20009079, 34546463). ClinVar contains an entry for this variant (Variation ID: 190934). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect SNTA1 function (PMID: 20009079). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197325	SCV001368004	uncertain significance	Long QT syndrome 12	2019-04-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4-P,BP5.
Ambry Genetics	RCV002399610	SCV002706474	likely benign	Cardiovascular phenotype	2022-06-07	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.
Fulgent Genetics, Fulgent Genetics	RCV001197325	SCV002793282	uncertain significance	Long QT syndrome 12	2021-11-09	criteria provided, single submitter	clinical testing