Submissions for variant NM_000335.5(SCN5A):c.2990C>A (p.Ala997Asp)

dbSNP: rs727503408

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151786	SCV000200238	uncertain significance	not specified	2020-09-09	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala997Asp variant in SCN5A has been identified in one individual with a sudden unexplained death (Wang 2014 PMID: 2463177). It has also been reported by other clinical laboratories in ClinVar (Variation ID 165149) and has been identified in 0.03% (9/30136) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4.
GeneDx	RCV000766460	SCV000589442	uncertain significance	not provided	2016-03-25	criteria provided, single submitter	clinical testing	The A997D variant was reported in a 4 week old male with autopsy-negative sudden unexplained death and was called a class 3 variant which may or may not be causative" (Wang et al., 2014); however familial segregation information, in vitro functional studies and additional clinical information was not included. In addition, the A997D variant has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (Landrum et al., 2014). The A997D variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A997D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign."
Color Diagnostics, LLC DBA Color Health	RCV001842470	SCV001352325	uncertain significance	Cardiac arrhythmia	2022-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 997 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden death (PMID: 24631775). This variant has been identified in 10/240014 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766460	SCV004292666	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 997 of the SCN5A protein (p.Ala997Asp). This variant is present in population databases (rs727503408, gnomAD 0.03%). This missense change has been observed in individual(s) with sudden infant death (PMID: 24631775). ClinVar contains an entry for this variant (Variation ID: 165149). 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.
All of Us Research Program, National Institutes of Health	RCV001842470	SCV004819122	uncertain significance	Cardiac arrhythmia	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 997 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden death (PMID: 24631775). This variant has been identified in 10/240014 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.