Submissions for variant NM_000335.5(SCN5A):c.5648C>T (p.Pro1883Leu)

dbSNP: rs755162776

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520769	SCV000616919	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SCN5A gene. The P1884L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 10/16512 (0.06%) alleles from individuals of South Asian ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The P1884L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520769	SCV000952832	uncertain significance	not provided	2023-10-28	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 1884 of the SCN5A protein (p.Pro1884Leu). This variant is present in population databases (rs755162776, gnomAD 0.06%). 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: 449118). 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	RCV001841409	SCV001734959	uncertain significance	Cardiac arrhythmia	2020-07-14	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1884 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 17/249280 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002350145	SCV002652053	likely benign	Cardiovascular phenotype	2022-06-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.