Submissions for variant NM_003098.3(SNTA1):c.770C>G (p.Ala257Gly)

gnomAD frequency: 0.00217  dbSNP: rs56157422

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171774	SCV000050786	likely benign	Long QT syndrome	2013-06-24	criteria provided, single submitter	research
Ambry Genetics	RCV000247418	SCV000318140	likely benign	Cardiovascular phenotype	2018-05-16	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	RCV000171774	SCV000563491	likely benign	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000191018	SCV000605231	uncertain significance	Long QT syndrome 12	2021-01-15	criteria provided, single submitter	clinical testing	The SNTA1 c.770C>G; p.Ala257Gly variant (rs56157422) is reported in the literature in individuals affected with long QT syndrome (Wu 2008) and carriers of the variant have been reported to have a slightly longer QTc interval than non-carriers (Ghouse 2015). However, this variant is also reported in healthy controls in combination with p.Pro74Leu (Cheng 2009), and functional studies suggest that the p.Pro74Leu variant rescues altered channel activity of the p.Ala257Gly variant alone (Cheng 2011). The p.Ala257Gly variant is reported in ClinVar (Variation ID: 191548), and is found in the non-Finnish European population with an allele frequency of 0.34% (442/128,676 alleles, including 3 homozygotes) in the Genome Aggregation Database. The alanine at codon 257 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.357). Due to conflicting information, the clinical significance of the p.Ala257Gly variant is uncertain at this time. References: Cheng J et al. Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. Circ Arrhythm Electrophysiol. 2009 Dec;2(6):667-76. Cheng J et al. LQTS-associated mutation A257G in a1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype. Cardiogenetics. 2011 Oct 25;1(1). pii: 136. Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Wu G et al. Alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):193-201.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000191018	SCV000743435	likely benign	Long QT syndrome 12	2016-07-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000990299	SCV001141232	benign	Long QT syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256962	SCV001433501	benign	not specified	2019-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001256962	SCV001623428	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: SNTA1 c.770C>G (p.Ala257Gly) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 251372 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 525.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. c.770C>G has been reported in the literature along with another SNTA1 variant, c.221C>T (p.Pro74Leu) in sequencing studies of individuals affected with Long QT Syndrome/Arrhythmia and/or in SIDS cohorts (example, Wu_2008, Ghouse_2015, Cheng_2009, Broendberg_2018). These data indicate that the variant may be associated with disease. At-least one co-occurrence with another pathogenic variant causative of Arrhythmia has been observed at our laboratory (KCNQ1 c.1686G>T, p.Arg562Ser), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function of the cardiac sodium channel (hNav1.5) (Wu_2008). Another study showed no damaging effect of this variant when present in conjunction with p.Pro74Leu. This variant combination reversed the peak sodium current and window current induced by the p.Arg257Gly variant alone (Cheng_2011). The following publications have been ascertained in the context of this evaluation (PMID: 23861362, 20009079, 24319568, 19684871, 29343803, 26159999). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=2; likely benign, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV001706109	SCV001942583	benign	not provided	2019-05-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25956966, 24319568, 19684871, 26159999, 16252003, 20009079, 25650408, 28988457, 29714131)
Dept of Medical Biology, Uskudar University	RCV000171774	SCV004022006	benign	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP3, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003917588	SCV004731520	likely benign	SNTA1-related disorder	2020-03-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000191018	SCV000245994	pathogenic	Long QT syndrome 12	2008-08-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV001706109	SCV001922034	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001256962	SCV001952846	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001706109	SCV001974708	likely benign	not provided		no assertion criteria provided	clinical testing