Submissions for variant NM_000335.5(SCN5A):c.2081A>G (p.Tyr694Cys)

gnomAD frequency: 0.00001  dbSNP: rs1438675647

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002269294	SCV000760274	uncertain significance	not provided	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 694 of the SCN5A protein (p.Tyr694Cys). This variant is present in population databases (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 532115). 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. 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	RCV001841841	SCV001358623	uncertain significance	Cardiac arrhythmia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 694 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with postpartum cardiomyopathy (PMID: 33874732). This variant has been identified in 2/280524 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	RCV001255579	SCV001432074	uncertain significance	not specified	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.2081A>G (p.Tyr694Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three 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 249120 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2081A>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002269294	SCV002552952	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics	RCV002420720	SCV002727781	uncertain significance	Cardiovascular phenotype	2024-02-13	criteria provided, single submitter	clinical testing	The p.Y694C variant (also known as c.2081A>G), located in coding exon 13 of the SCN5A gene, results from an A to G substitution at nucleotide position 2081. The tyrosine at codon 694 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in a peripartum cardiomyopathy cohort; however, details were limited (Goli R et al. Circulation, 2021 May;143:1852-1862). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001841841	SCV004840863	uncertain significance	Cardiac arrhythmia	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 694 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with postpartum cardiomyopathy (PMID: 33874732). This variant has been identified in 2/280524 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.