Submissions for variant NM_000335.5(SCN5A):c.5171C>T (p.Pro1724Leu)

gnomAD frequency: 0.00002  dbSNP: rs199473301

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842379	SCV001341294	uncertain significance	Cardiac arrhythmia	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1725 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 individuals affected with Brugada syndrome (PMID: 26173111, 32268277, DOI:10.1186/s42444-022-00077-9). It has also been reported in an individual affected with long QT syndrome (PMID: 19862833). This variant has been identified in 5/251170 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	RCV001529380	SCV002192078	uncertain significance	not provided	2023-12-14	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 1725 of the SCN5A protein (p.Pro1725Leu). This variant is present in population databases (rs199473301, gnomAD 0.01%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 19862833, 26173111). ClinVar contains an entry for this variant (Variation ID: 67962). 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.
All of Us Research Program, National Institutes of Health	RCV001842379	SCV004827246	uncertain significance	Cardiac arrhythmia	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1725 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 individuals affected with Brugada syndrome (PMID: 26173111, 32268277, DOI:10.1186/s42444-022-00077-9). It has also been reported in an individual affected with long QT syndrome (PMID: 19862833). This variant has been identified in 5/251170 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	RCV004019059	SCV004944530	uncertain significance	Cardiovascular phenotype	2021-08-09	criteria provided, single submitter	clinical testing	The c.5174C>T (p.P1725L) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 5174, causing the proline (P) at amino acid position 1725 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV004668766	SCV005094553	uncertain significance	Dilated cardiomyopathy 1E	2024-07-03	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058748	SCV000090268	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19862833). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529380	SCV001742723	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529380	SCV001958048	uncertain significance	not provided		no assertion criteria provided	clinical testing