Submissions for variant NM_003098.3(SNTA1):c.221C>T (p.Pro74Leu)

gnomAD frequency: 0.00198  dbSNP: rs572545726

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000252164	SCV000318141	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.
Illumina Laboratory Services, Illumina	RCV000624992	SCV000433519	likely benign	Long QT syndrome 12	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000434724	SCV000514718	benign	not specified	2015-06-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000406481	SCV000563486	likely benign	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000624992	SCV000605232	uncertain significance	Long QT syndrome 12	2021-01-15	criteria provided, single submitter	clinical testing	The SNTA1 c.221C>T; p.Pro74Leu variant (rs572545726) is reported in the literature in combination with the p.Ala257Gly variant in several healthy controls (Cheng 2009). Functional studies suggest that the p.Pro74Leu variant rescues the in vitro channel activity defect of the p.Ala257Gly variant, but has no effect on channel activity on its own (Cheng 2011). The p.Pro74Leu variant is reported in ClinVar (Variation ID: 263476) and is found in the non-Finnish European population with an allele frequency of 0.40% (98/24572 alleles) in the Genome Aggregation Database. The proline at codon 74 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.055). While the evidence suggests the p.Pro74Leu does not cause disease and may ameliorate the effects of the p.Ala257Gly, given the lack of clinical and functional data, the significance of the p.Pro74Leu variant cannot be determined with certainty. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000624992	SCV000743437	likely benign	Long QT syndrome 12	2017-08-18	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852950	SCV000995697	likely benign	Ventricular tachycardia	2018-09-15	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000434724	SCV001433500	likely benign	not specified	2019-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000434724	SCV001623429	likely benign	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: SNTA1 c.221C>T (p.Pro74Leu) results in a non-conservative amino acid change located in the pleckstrin homology domain (IPR001849) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 20944 control chromosomes. The observed variant frequency is approximately 224.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.221C>T has been reported in the literature along with another SNTA1 variant, c.770C>G (p.Ala257Gly) in sequencing studies of individuals affected with Arrhythmia and/or in SIDS cohorts (example, Cheng_2009, Broendberg_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. 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. These results showed no damaging effect of this variant as it was demonstrated to have a rescue function when present in conjunction with (p.Arg257Gly). 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: 20009079, 25650408, 24319568, 29343803). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=1; likely benign, n=8, VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003920009	SCV004732291	likely benign	SNTA1-related disorder	2020-10-19	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).
Clinical Genetics, Academic Medical Center	RCV000857623	SCV001918447	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000857623	SCV001953839	likely benign	not provided		no assertion criteria provided	clinical testing