Submissions for variant NM_000335.5(SCN5A):c.2876T>C (p.Leu959Pro)

gnomAD frequency: 0.00001  dbSNP: rs1276970820

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002223919	SCV000828050	uncertain significance	not provided	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 959 of the SCN5A protein (p.Leu959Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 576769). 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 disruptive. 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	RCV001841868	SCV001354873	uncertain significance	Cardiac arrhythmia	2019-11-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 959 of the SCN5A protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/248026 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223919	SCV002502596	uncertain significance	not provided	2021-10-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001841868	SCV004826235	uncertain significance	Cardiac arrhythmia	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 959 of the SCN5A protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/248026 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	RCV004659181	SCV005159794	uncertain significance	Cardiovascular phenotype	2024-05-10	criteria provided, single submitter	clinical testing	The p.L959P variant (also known as c.2876T>C), located in coding exon 16 of the SCN5A gene, results from a T to C substitution at nucleotide position 2876. The leucine at codon 959 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.