Submissions for variant NM_003098.3(SNTA1):c.1088A>C (p.Glu363Ala)

gnomAD frequency: 0.00017  dbSNP: rs147964932

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171101	SCV000223666	uncertain significance	not provided	2019-09-06	criteria provided, single submitter	clinical testing	Reported in an individual with a prolonged QTc, ventricular tachycardia, a clinical diagnosis of Marfan syndrome, and a history of sudden cardiac arrest; however, this proband was also found to harbor a de novo TGFBR2 variant, and this proband's unaffected mother was also heterozygous for this SNTA1 variant (Extramiana et al., 2018); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 190918; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30158670)
Ambry Genetics	RCV000243691	SCV000319579	likely benign	Cardiovascular phenotype	2019-10-18	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	RCV000796538	SCV000936057	uncertain significance	Long QT syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 363 of the SNTA1 protein (p.Glu363Ala). This variant is present in population databases (rs147964932, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 190918). 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. 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.
Illumina Laboratory Services, Illumina	RCV001138961	SCV001299056	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155101	SCV003844628	likely benign	not specified	2023-02-13	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656217	SCV000678411	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome