Submissions for variant NM_000335.5(SCN5A):c.3316G>A (p.Glu1106Lys)

gnomAD frequency: 0.00005  dbSNP: rs199473193

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058564	SCV001049848	likely benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000987210	SCV001136459	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000058564	SCV001814133	likely benign	not provided	2019-09-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31043699, 22581653, 20129283, 16453024, 19841300)
Color Diagnostics, LLC DBA Color Health	RCV003591670	SCV004361659	uncertain significance	Cardiac arrhythmia	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1107 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 been reported in two unrelated individuals affected with sudden unexpected death in pediatrics (PMID: 16453024, 32449611), as well as in two healthy Asian control individuals (PMID: 19841300, 20129283). This variant has been identified in 33/244554 chromosomes ( 31/30138 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for SCN5A-related disorders, 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
All of Us Research Program, National Institutes of Health	RCV003591670	SCV004824939	uncertain significance	Cardiac arrhythmia	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1107 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 been reported in two unrelated individuals affected with sudden unexpected death in pediatrics (PMID: 16453024, 32449611), as well as in two healthy Asian control individuals (PMID: 19841300, 20129283). This variant has been identified in 33/244554 chromosomes ( 31/30138 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for SCN5A-related disorders, 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	RCV005406800	SCV006071538	likely benign	not specified	2025-03-24	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.3319G>A (p.Glu1107Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 244554 control chromosomes, predominantly at a frequency of 0.001 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Brugada Syndrome phenotype (0.00017). To our knowledge, no occurrence of c.3319G>A in individuals affected with Brugada Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 67790). Based on the evidence outlined above, the variant was classified as likely benign.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058564	SCV000090084	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:16453024;PMID:20129283).