Submissions for variant NM_000335.5(SCN5A):c.5605G>A (p.Ala1869Thr)

gnomAD frequency: 0.00001  dbSNP: rs794728939

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003488436	SCV000835181	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 201595). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 23631430). This variant is present in population databases (rs794728939, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1870 of the SCN5A protein (p.Ala1870Thr).
Color Diagnostics, LLC DBA Color Health	RCV001842940	SCV001348611	uncertain significance	Cardiac arrhythmia	2023-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1870 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 an individual referred for long QT syndrome genetic testing (PMID: 23631430). This variant has been identified in 2/249268 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	RCV002345638	SCV002651432	uncertain significance	Cardiovascular phenotype	2023-03-30	criteria provided, single submitter	clinical testing	The p.A1870T variant (also known as c.5608G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5608. The alanine at codon 1870 is replaced by threonine, an amino acid with similar properties. This variant has been detected in a long QT syndrome genetic testing cohort, and in a cohort not selected for the presence of cardiovascular disease; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Diebold I et al. Hum Mutat. 2020 May;41(5):1025-1032). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003389319	SCV004101489	uncertain significance	Long QT syndrome 3		criteria provided, single submitter	clinical testing	The missense variant p.A1869T in SCN5A (NM_000335.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.A1869T variant is observed in 2/1,13,022 (0.0018%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between alanine and threonine, which is not likely to impact secondary protein structure as these residues share similar properties.The variant has been reported to ClinVar as Uncertain Significance. For these reasons, this variant has been classified as Uncertain Significance. Disease causing variants in SCN5A have also been reported in Brugada syndrome,Heart Block, cardiomyopathy and ventricular fibrillation
Revvity Omics, Revvity	RCV003488436	SCV004237176	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842940	SCV004815181	uncertain significance	Cardiac arrhythmia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1870 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 an individual referred for long QT syndrome genetic testing (PMID: 23631430). This variant has been identified in 2/249268 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.