Submissions for variant NM_000335.5(SCN5A):c.5065G>A (p.Asp1689Asn)

gnomAD frequency: 0.00001  dbSNP: rs1060499900

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455733	SCV000540273	uncertain significance	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Functional study suggests pathogenicity, but no segs and only 1 proband; Absent from ExAC
Labcorp Genetics (formerly Invitae), Labcorp	RCV004591283	SCV000637169	uncertain significance	not provided	2024-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1690 of the SCN5A protein (p.Asp1690Asn). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 23085483, 27108952, 30203441, 32893267, 34546463). This variant is also known as c.4906G>A (p.Asp1636Asn). ClinVar contains an entry for this variant (Variation ID: 403420). 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: 23085483, 27108952). 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	RCV001841342	SCV001342230	uncertain significance	Cardiac arrhythmia	2023-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1690 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). Functional studies have shown that this variant causes reduced channel trafficking to the plasma membrane, decreased sodium channel current density, positive shift of activation, and slower recovery from inactivation (PMID: 23085483, 23085483, 30232268). This variant has been reported in at least three unrelated individuals affected with Brugada syndrome (PMID: 23085483, 26173111, 27108952, 32268277, 32893267). One of these individuals carried a pathogenic c.3840+1G>A variant in the same gene that could explain the observed phenotype (PMID: 26173111). This variant has been identified in 1/251488 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	RCV000455733	SCV003845082	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5068G>A (p.Asp1690Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251488 control chromosomes. c.5068G>A has been reported in the literature in individuals affected with Brugada Syndrome (e.g. Nunez_2013). In one family, this variant does not co-segregate with Brugada Syndrome (Zeng_2016). Co-occurrence with a pathogenic variant has been reported (TTN c.48868C>T, p.Arg16290X, internal database), providing supporting evidence for a benign role. Three publications report experimental evidence evaluating an impact on protein function and showed that this variant affect SCN5A function (Nunez_2013, Zeng_2016), however, this effect may not associate with BrS clinical phenotype (Pearman_2020). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Institute of Immunology and Genetics Kaiserslautern	RCV003509541	SCV004363641	likely pathogenic	Brugada syndrome 1	2024-01-31	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PM1, PP3, PP5; Variant was found in heterozygous state
All of Us Research Program, National Institutes of Health	RCV001841342	SCV004832853	uncertain significance	Cardiac arrhythmia	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1690 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). Functional studies have shown that this variant causes reduced channel trafficking to the plasma membrane, decreased sodium channel current density, positive shift of activation, and slower recovery from inactivation (PMID: 23085483, 23085483, 30232268). This variant has been reported in at least three unrelated individuals affected with Brugada syndrome (PMID: 23085483, 26173111, 27108952, 32268277, 32893267). One of these individuals carried a pathogenic c.3840+1G>A variant in the same gene that could explain the observed phenotype (PMID: 26173111). This variant has been identified in 1/251488 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.
Ambry Genetics	RCV004022538	SCV005031251	uncertain significance	Cardiovascular phenotype	2024-01-24	criteria provided, single submitter	clinical testing	The p.D1690N variant (also known as c.5068G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5068. The aspartic acid at codon 1690 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in several individuals with Brugada syndrome; however, in two cases it co-occurred with other alterations in SCN5A (Núñez L et al. Heart Rhythm, 2013 Feb;10:264-72; Selga E et al. PLoS ONE, 2015 Jul;10:e0132888; Zeng Z et al. Mol Med Rep, 2016 Jun;13:5216-22). In vitro functional studies suggest this alteration results in reduced sodium current, but such studies do not always reflect function in vivo (Núñez L et al. Heart Rhythm, 2013 Feb;10:264-72; Zeng Z et al. Mol Med Rep, 2016 Jun;13:5216-22; Pérez-Hernández M et al. JCI Insight, 2018 Sep;3: pii: 96291). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004591283	SCV005077995	uncertain significance	not provided	2023-12-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); A published functional study suggests that the p.(D1690N) variant results in loss-of-function phenotype (PMID: 27108952); 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: 23085483, 30662450, 30203441, 33131149, 34546463, 32268277, 26173111, 27108952)