Submissions for variant NM_000335.5(SCN5A):c.5687G>A (p.Arg1896Gln)

gnomAD frequency: 0.00001  dbSNP: rs761369505

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766545	SCV000545094	uncertain significance	not provided	2025-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1897 of the SCN5A protein (p.Arg1897Gln). This variant is present in population databases (rs761369505, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 27485560). ClinVar contains an entry for this variant (Variation ID: 406444). 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. 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	RCV000622063	SCV000737758	uncertain significance	Cardiovascular phenotype	2022-02-15	criteria provided, single submitter	clinical testing	The c.5690G>A (p.R1897Q) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 5690, causing the arginine (R) at amino acid position 1897 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (6/280678) total alleles studied. The highest observed frequency was 0.01% (3/30602) of South Asian alleles. This alteration has been reported in one subject with long QT syndrome (LQTS) who was also homozygous for a missense alteration in KCNQ1 (Vyas, 2016). This variant was also reported in a pediatric genetics case who had a co-occurring SCN5A gross deletion; however, clinical details were not provided (Truty, 2019). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001841360	SCV001352083	uncertain significance	Cardiac arrhythmia	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1897 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 performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 27485560). This variant has been identified in 6/280678 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.
Fulgent Genetics, Fulgent Genetics	RCV002496752	SCV002792589	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	2021-09-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001841360	SCV004828772	uncertain significance	Cardiac arrhythmia	2024-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1897 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 performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 27485560). This variant has been identified in 6/280678 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.
GeneDx	RCV003766545	SCV005421427	uncertain significance	not provided	2024-06-07	criteria provided, single submitter	clinical testing	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: 29895855, 27485560)