Submissions for variant NM_000335.5(SCN5A):c.1340C>G (p.Ala447Gly)

gnomAD frequency: 0.00024  dbSNP: rs199473113

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155813	SCV000205524	uncertain significance	not specified	2018-04-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000058416	SCV000235366	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Variant has not been reported in association with a SCN5A-related disorder, but has been reported in one African control sample (Ackerman et al., 2004; Kapa et al., 2009; Kapplinger et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20129283, 15851227, 19841300, 22581653)
Invitae	RCV000058416	SCV000637077	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 447 of the SCN5A protein (p.Ala447Gly). This variant is present in population databases (rs199473113, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 67657). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842276	SCV001353527	uncertain significance	Cardiac arrhythmia	2023-03-10	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 447 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 19/272122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155813	SCV001426938	uncertain significance	not specified	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.1340C>G (p.Ala447Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 262936 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in SCN5A causing Arrhythmia (7.2e-05 vs 0.0001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1340C>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001332809	SCV001525228	uncertain significance	Brugada syndrome 1	2019-08-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002381373	SCV002693647	likely benign	Cardiovascular phenotype	2022-08-25	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224131	SCV003920447	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-03-30	criteria provided, single submitter	clinical testing	SCN5A NM_198056.2 exon 11 p.Ala447Gly (c.1340C>G): This variant has not been reported in the literature, but it is present in 17/23260 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs199473113). This variant is present in ClinVar (Variation ID:67657). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058416	SCV004564468	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	The SCN5A c.1340C>G; p.Ala447Gly variant (rs199473113) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (Lopes 2015). However, this variant has also been reported in healthy individuals (Kapa 2009, Kapplinger 2010, Kapplinger 2015). This variant is also reported in ClinVar (Variation ID: 67657) and is found in the African/African-American population with an allele frequency of 0.07% (17/23416 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.538). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. PMID: 19841300. Kapplinger JD et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010 Jan;7(1):33-46. PMID: 20129283. Kapplinger JD et al. Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95. PMID: 25904541. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Epub 2014 Oct 28. PMID: 25351510.
All of Us Research Program, National Institutes of Health	RCV001842276	SCV004822711	uncertain significance	Cardiac arrhythmia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 447 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 19/272122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058416	SCV000089936	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).