Submissions for variant NM_000335.5(SCN5A):c.5454_5455inv (p.Ala1819Thr)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638699	SCV000760241	uncertain significance	Brugada syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1820 of the SCN5A protein (p.Ala1820Thr). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. 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: 532094). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780705	SCV000918198	uncertain significance	not specified	2018-10-15	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5457_5458delinsCA (p.Ala1820Thr) results in a amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was reported in gnomad as two different SNPs (3:38592405 C / T, 3:38592405 C / T), however from the reads provided it is likely that all 5 heterozygotes have both variants present (frequency of 2e-05 in 246198 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.5457_5458delinsCA in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001841837	SCV001358622	uncertain significance	Cardiac arrhythmia	2022-09-28	criteria provided, single submitter	clinical testing	This variant replaces alanine with threonine at codon 1820 of the SCN5A protein. To our knowledge, functional assays have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders. A different DNA change (c.5458G>A) resulting in the same amino acid change as this variant has been reported in an individual affected with Brugada syndrome (Detta 2010, dissertation, University of Naples Federico II). This variant has also been identified in 5/249718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	RCV002492987	SCV002787081	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	2021-08-05	criteria provided, single submitter	clinical testing