ClinVar Miner

Submissions for variant NM_003098.2(SNTA1):c.770C>G (p.Ala257Gly) (rs56157422)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
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 Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000171774 SCV000563491 likely benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000191018 SCV000605231 uncertain significance Long QT syndrome 12 2018-12-17 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), but has also been reported in in carriers with a slightly longer QTc interval (Ghouse 2015). Additionally, this variant is found in healthy controls when found in combination with p.Pro74Leu, and functional studies suggest that the p.Pro74Leu variant rescues the in vitro channel activity defect of the p.Ala257Gly variant (Cheng 2011). This 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, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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 uncertain significance Long QT syndrome 1 2019-05-28 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 2021-05-16 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 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).Six 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.
OMIM RCV000191018 SCV000245994 pathogenic Long QT syndrome 12 2008-08-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.