Submissions for variant NM_000335.5(SCN5A):c.2039G>A (p.Arg680His)

gnomAD frequency: 0.00002  dbSNP: rs199473142

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156507	SCV000206226	likely benign	not specified	2014-04-24	criteria provided, single submitter	clinical testing	Arg680His exon 14 of SCN5A: This variant has been identified in 2 cases of sudd en death, 1 Norwegian infant and 1 Black adult whom also carried another variant in SCN5A (Anestad 2007, Tester 2012) and was absent from large population studi es. Studies in HEK293 cells have shown that the Arg680His variant may impact pro tein function (Cheng 2011) though this type of assay often does not accurately r epresent biological function. However, it is not expected to have clinical signi ficance due to a lack of evolutionary conservation. Of note, >30 species includi ng mammals have a histidine (His) at this position despite high nearby amino aci d conservation. In summary, this variant is likely benign but a modifying role c annot be exluded.
Color Diagnostics, LLC DBA Color Health	RCV001842306	SCV000904467	likely benign	Cardiac arrhythmia	2018-08-28	criteria provided, single submitter	clinical testing
Invitae	RCV001699115	SCV002110322	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 680 of the SCN5A protein (p.Arg680His). This variant is present in population databases (rs199473142, gnomAD 0.007%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 17210839, 21385947, 33221895). ClinVar contains an entry for this variant (Variation ID: 67706). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 17210841). 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058473	SCV000089993	not provided	SUDDEN INFANT DEATH SYNDROME		no assertion provided	literature only	This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:17210839;PMID:21385947;PMID:17210841;PMID:22677073). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Genetics, Academic Medical Center	RCV001699115	SCV001920057	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699115	SCV001975769	likely benign	not provided		no assertion criteria provided	clinical testing