Submissions for variant NM_000335.5(SCN5A):c.1231G>A (p.Val411Met)

dbSNP: rs72549410

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182964	SCV000235361	pathogenic	not provided	2019-07-08	criteria provided, single submitter	clinical testing	Reported in several individuals with LQTS, including multiple cases of apparent de novo occurrence, as the variant was not detected in parents (Priori et al., 2000; Tester et al., 2005; Hofman-Bang et al., 2006; Horne et al., 2011; Carrasco et al., 2012; Crotti et al., 2012; Medlock et al., 2012; Stattin et al., 2012; Christiansen et al., 2014; Zhou et al., 2015; Itoh et al., 2016; Vyas et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID 67651; Landrum et al., 2016); Published functional studies in cultured cells show that V411M causes a gain of function effect on the sodium channel (Horne et al., 2011; Zhou et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30059973, 31257342, 32161207, 21193062, 22721569, 23098067, 26888838, 27485560, 28588847, 25904541, 26669661, 10961955, 22885918, 15840476, 16712702, 24606995, 19716085, 23158531, 31737537, 32383558)
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000234790	SCV000240230	pathogenic	Long QT syndrome 3	2013-01-01	criteria provided, single submitter	research
Invitae	RCV000182964	SCV000253977	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 411 of the SCN5A protein (p.Val411Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 10961955, 15840476, 16712702, 19716085, 21193062, 23098067, 23158531, 24709866). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 67651). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 21193062). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000621361	SCV000737789	pathogenic	Cardiovascular phenotype	2016-11-11	criteria provided, single submitter	clinical testing	The p.V411M pathogenic mutation (also known as c.1231G>A), located in coding exon 9 of the SCN5A gene, results from a G to A substitution at nucleotide position 1231. The valine at codon 411 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with long QT syndrome (Priori SG et al. Circulation. 2000;102:945-7; Hofman-Bang J et al. Clin Genet. 2006;69:504-11; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Horne AJ et al. Heart Rhythm. 2011;8:770-7; Carrasco JI et al. Rev Esp Cardiol (Engl Ed). 2012;65:1058-9; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Crotti L et al. J Am Coll Cardiol. 2012;60:2515-24; Abrams DJ et al. Circulation. 2014;129:1524-9). This alteration was described as occurring de novo in two unrelated cases, and, in a third case, the alteration was detected in two affected siblings, but not in the unaffected parents (Horne AJ et al. Heart Rhythm. 2011;8:770-7; Carrasco JI et al. Rev Esp Cardiol (Engl Ed). 2012;65:1058-9; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95). Based on internal structural analysis, this alteration is anticipated to result in a decrease in structural stability (Wu J et al. Science. 2015;350(6267):aad2395In). In addition, in vitro studies have suggested that this alteration may alter channel activities (Horne AJ et al. Heart Rhythm. 2011;8:770-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000157478	SCV000740425	pathogenic	Long QT syndrome	2017-06-26	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000234790	SCV000805142	pathogenic	Long QT syndrome 3	2018-02-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000234790	SCV003921975	pathogenic	Long QT syndrome 3	2020-11-05	criteria provided, single submitter	clinical testing	0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, where missense have been shown to both impair and improve channel current activity (OMIM, PMID: 29806494). (N) 0108 - This gene is known to be associated with both recessive and dominant disease, where recessive disease has few reports and there is no clear genotype-phenotype correlation (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 10). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools. (P) 0600 - Variant is located in an annotated domain or motif, (S6 of the ion transporter domain I; PMID:21193062). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in multiple de novo individuals with Long QT syndrome (ClinVar, LOVD, PMID:31257342, PMID:21193062). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function, where transfected HEK293 cells demonstrated hyperpolarizing shifts in conductance voltage (PMID:21193062). (P) 1205 - Variant is maternally inherited. The variant is mosaic in this patient's mother at an allele fraction of approximately 12-14%. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Dept of Medical Biology, Uskudar University	RCV000157478	SCV004022043	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PS2_Strong, PS3_Moderate, PM2, PP3
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058408	SCV000089928	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10961955;PMID:15840476;PMID:16712702;PMID:19716085;PMID:21193062). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Blueprint Genetics	RCV000157478	SCV000207223	pathogenic	Long QT syndrome	2014-07-23	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000182964	SCV001925771	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000182964	SCV001957442	pathogenic	not provided		no assertion criteria provided	clinical testing