Submissions for variant NM_000335.5(SCN5A):c.5333C>T (p.Thr1778Met)

gnomAD frequency: 0.00008  dbSNP: rs199473634

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000786219	SCV000235525	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	Reported in association with various phenotypes, including LQTS, Brugada syndrome, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), atrial fibrillation, and cardiac arrest (PMID: 15840476, 20129283, 25351510, 28416588, 31638414, 36964972); In vitro functional studies suggested that the p.(T1779M) variant demonstrates channel function similar to wild-type (PMID: 25904541); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T1778M) due to the use of an alternate transcript; This variant is associated with the following publications: (PMID: 25637381, 24055113, 19862833, 22378279, 20129283, 25351510, 25904541, 28150151, 26986070, 19716085, 19841300, 28416588, 28567303, 27566755, 31638414, 34426522, 30203441, 15840476, 36964972, 34643236)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000786219	SCV000545029	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1779 of the SCN5A protein (p.Thr1779Met). This variant is present in population databases (rs199473634, gnomAD 0.006%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15840476, 19716085, 19841300, 20129283, 27566755, 28416588). ClinVar contains an entry for this variant (Variation ID: 67985). 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 does not substantially affect SCN5A function (PMID: 25904541). 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.
Ambry Genetics	RCV000617171	SCV000738199	uncertain significance	Cardiovascular phenotype	2024-11-25	criteria provided, single submitter	clinical testing	The p.T1779M variant (also known as c.5336C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 5336. The threonine at codon 1779 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in long QT syndrome and hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Lopes LR et al. Heart, 2015 Feb;101:294-301). Additionally, this alteration has been detected in a dilated cardiomyopathy cohort and an atrial fibrillation cohort (Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Goodyer WR et al. Circ Genom Precis Med, 2019 11;12:e002713). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001146112	SCV001306832	uncertain significance	Dilated cardiomyopathy 1E	2019-08-02	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146113	SCV001306833	uncertain significance	Progressive familial heart block, type 1A	2019-08-02	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146114	SCV001306834	likely benign	Sick sinus syndrome 1	2019-08-02	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001146115	SCV001306835	uncertain significance	Brugada syndrome 1	2019-08-02	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146116	SCV001306836	uncertain significance	Long QT syndrome 3	2019-08-02	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146117	SCV001306837	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2019-08-02	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183115	SCV001337777	uncertain significance	not specified	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5336C>T (p.Thr1779Met) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 303096 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. c.5336C>T has been reported in the literature in individuals affected with long QT syndrome, dilated cardiomyopathy and Brugada syndrome (ie. Tester_2005, Kapplinger_2009, Kapa_2009, Stavropoulos_2016, Dal Ferro_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one functional study reports this variant has no impact on protein function (Kapplinger_2016). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV001842384	SCV001350459	uncertain significance	Cardiac arrhythmia	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Thr1778Met using another transcript NM_000335.5) replaces threonine with methionine at codon 1779 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study has shown that this variant does not have a significant impact on the protein function (PMID: 25904541). This variant has been reported in six individuals affected with long QT syndrome (PMID: 19841300, 27566755), in three individuals referred for long QT syndrome (PMID: 15840476, 19716085), in one individual referred for Brugada syndrome testing (PMID: 20129283), in one individual affected with very early onset atrial fibrillation (PMID: 31638414), and in a control subject (PMID: 25904541). This variant has also been identified in 12/282546 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001146116	SCV001435337	uncertain significance	Long QT syndrome 3	2020-07-16	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001146116	SCV002581605	uncertain significance	Long QT syndrome 3	2022-04-01	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058771	SCV000090291	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:15840476;PMID:19716085;PMID:19841300;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148849	SCV000190592	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786219	SCV000924953	uncertain significance	not provided	2017-04-05	no assertion criteria provided	provider interpretation
Clinical Genetics, Academic Medical Center	RCV000786219	SCV001925436	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000786219	SCV001971558	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000786219	SCV001979583	uncertain significance	not provided		no assertion criteria provided	clinical testing