Submissions for variant NM_000335.5(SCN5A):c.4129G>A (p.Val1377Met)

gnomAD frequency: 0.00001  dbSNP: rs748312802

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208068	SCV000264209	likely pathogenic	Brugada syndrome	2015-05-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842962	SCV001734466	uncertain significance	Cardiac arrhythmia	2022-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1378 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). A functional study has shown that this variant causes trafficking defects resulting in dramatically reduced current density without changes in the kinetics and gating properties of the channel (PMID: 22529811). This variant has been reported in one individual affected with Brugada syndrome (PMID: 22529811) and in an asymptomatic older individual without a history of cardiovascular events (PMID: 34135346). This variant has been identified in 1/250942 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541646	SCV003262245	uncertain significance	not provided	2024-03-03	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 1378 of the SCN5A protein (p.Val1378Met). This variant is present in population databases (rs748312802, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 22529811). ClinVar contains an entry for this variant (Variation ID: 222809). 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: 22529811). 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.
All of Us Research Program, National Institutes of Health	RCV000208068	SCV004830283	uncertain significance	Brugada syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This variant has been reported in one individual with Brugada syndrome to date (PMID: 22529811). Functional studies suggest that this variant results in a deleterious effect on the protein; however, sufficient controls or replicates were not incorporated (PMID: 22529811). This variant is present in 1/250942 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786556	SCV005399383	uncertain significance	Long QT syndrome 3	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ion transport domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by a clinical diagnostic laboratory for Brugada syndrome and reported in one individual with Brugada syndrome (ClinVar; PMID: 22529811). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into tsA201 cell lines demonstrated severe reduction in current density but with normal gating properties compared to WT constructs, likely due to retention of channel proteins to ER. Treatment of the mutant cellls with mexiletine, a drug known to correct NaV1.5 trafficking defects, partially reversed ER retention resulting in partially restored current density (PMID: 22529811). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign