Submissions for variant NM_000335.5(SCN5A):c.2614G>A (p.Asp872Asn)

gnomAD frequency: 0.00001  dbSNP: rs763396298

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183006	SCV000235412	uncertain significance	not provided	2024-08-05	criteria provided, single submitter	clinical testing	Identified in individuals with various cardiac presentations, including hypertrophic cardiomyopathy (HCM), Brugada syndrome, LQTS, and unexplained sudden cardiac arrest, referred for genetic testing at GeneDx and in published literature (PMID: 26656175, 30847666, 32091595); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect by reduction of peak sodium current density and slower recovery from inactivation (PMID: 32091595); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26656175, 30847666, 35932045, 32091595)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183006	SCV001236021	uncertain significance	not provided	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 872 of the SCN5A protein (p.Asp872Asn). This variant is present in population databases (rs763396298, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 26656175, 32091595). ClinVar contains an entry for this variant (Variation ID: 201476). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32091595). 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	RCV001842907	SCV001359812	uncertain significance	Cardiac arrhythmia	2021-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 872 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant to cause partial loss of sodium channel function (PMID: 32091595). This variant has not been reported in individuals affected with Brugada syndrome or long QT syndrome. This variant has been reported in an unexplained sudden cardiac arrest survivor (PMID: 32091595) and two first-degree relatives affected with hypertrophic cardiomyopathy (Cronin et al., 2018. http://dx.doi.org/10.1136/heartjnl-2018-ICS.20). This variant has been identified in 4/251154 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	RCV000183006	SCV002501913	uncertain significance	not provided	2021-08-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433807	SCV002745261	uncertain significance	Cardiovascular phenotype	2021-06-30	criteria provided, single submitter	clinical testing	The p.D872N variant (also known as c.2614G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2614. The aspartic acid at codon 872 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in a subject with hypertrophic cardiomyopathy and in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (Bottillo I et al. Gene, 2016 Feb;577:227-35; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant was also detected in a subject with sudden cardiac arrest and was reported to have a possible impact on protein function (Giudicessi JR et al. Europace, 2020 04;22:622-631). This amino acid position is not well conserved in available vertebrate species, and asparagine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.