Submissions for variant NM_000335.5(SCN5A):c.3032C>T (p.Pro1011Leu)

gnomAD frequency: 0.00006  dbSNP: rs369249772

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455892	SCV000540276	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD, classified as VUS; ExAC: 1/8218 East Asian chromosomes
Color Diagnostics, LLC DBA Color Health	RCV001841343	SCV001359453	uncertain significance	Cardiac arrhythmia	2023-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1011 of the SCN5A protein. Computational prediction suggests that this variant may have a 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 infant affected with sudden death (PMID: 24631775, 29247119) and in individuals suspected to be affected with epilepsy (PMID: 31696929). This variant has been identified in 9/275824 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	RCV002436370	SCV002753185	uncertain significance	Cardiovascular phenotype	2023-03-29	criteria provided, single submitter	clinical testing	The p.P1011L variant (also known as c.3032C>T), located in coding exon 16 of the SCN5A gene, results from a C to T substitution at nucleotide position 3032. The proline at codon 1011 is replaced by leucine, an amino acid with similar properties. This variant has been detected in a sudden unexplained death cohort, in a control cohort of presumed healthy individuals, and in individuals from an epilepsy cohort; however, details were limited (Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10; Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Li X et al. Ann Hum Genet. 2020 Mar;84(2):161-168). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541743	SCV003286093	uncertain significance	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1011 of the SCN5A protein (p.Pro1011Leu). This variant is present in population databases (rs369249772, gnomAD 0.01%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 24631775). ClinVar contains an entry for this variant (Variation ID: 403421). 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 leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001841343	SCV004833264	uncertain significance	Cardiac arrhythmia	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1011 of the SCN5A protein. Computational prediction suggests that this variant may have a 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 infant affected with sudden death (PMID: 24631775, 29247119) and in individuals suspected to be affected with epilepsy (PMID: 31696929). This variant has been identified in 9/275824 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.
GeneDx	RCV003541743	SCV005081122	uncertain significance	not provided	2024-02-23	criteria provided, single submitter	clinical testing	Identified in an infant with sudden unexplained death, but familial segregation information and additional clinical information was not provided (PMID: 24631775); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119, 24631775)