Submissions for variant NM_000335.5(SCN5A):c.5969G>A (p.Arg1990Gln)

gnomAD frequency: 0.00004  dbSNP: rs199473336

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000058820	SCV000205416	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing	The p.Arg1991Gln variant in SCN5A has been identified by our laboratory in 1 African American individual with LVNC (also reported in Mazzarotto 2021). This variant has also been identified in 1/2600 Black control chromosomes (Kapa 2007, Kapplinger 2010), 1/15000 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org), and 1/198 Kenyan chromosomes by the 1000 Genomes project (dbSNP rs199473336). This variant has also been reported in ClinVar (Variation ID 68021). Computational prediction tools and conservation analysis suggest that the p.Arg1991Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg1991Gln variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058820	SCV000545101	uncertain significance	not provided	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1991 of the SCN5A protein (p.Arg1991Gln). This variant is present in population databases (rs199473336, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 17438610, 33500567). ClinVar contains an entry for this variant (Variation ID: 68021). 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. 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	RCV001842401	SCV001355709	uncertain significance	Cardiac arrhythmia	2023-01-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1991 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 17438610, 21185501), as well as in several ostensibly healthy individuals (PMID: 19841300, 20129283, 25904541, Aguib et al., 2019). This variant has been identified in 2/31398 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	RCV000058820	SCV001772393	uncertain significance	not provided	2020-05-22	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance by several clinical laboratories; reportedly identified in a patient with DCM who also harbored a likely pathogenic variant in the LMNA gene (ClinVar Variant ID#68021; SCV000924943.1; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32048431, 25904541, 26332594, 20129283, 19841300)
Fulgent Genetics, Fulgent Genetics	RCV002483115	SCV002782729	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162460	SCV003903668	uncertain significance	Cardiovascular phenotype	2022-11-10	criteria provided, single submitter	clinical testing	The c.5972G>A (p.R1991Q) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 5972, causing the arginine (R) at amino acid position 1991 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001842401	SCV004815172	uncertain significance	Cardiac arrhythmia	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1991 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 17438610, 21185501), as well as in several ostensibly healthy individuals (PMID: 19841300, 20129283, 25904541, Aguib et al., 2019). This variant has been identified in 2/31398 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058820	SCV000090340	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:17438607;PMID:19841300;PMID:20129283).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000058820	SCV000924943	uncertain significance	not provided	2016-06-06	no assertion criteria provided	provider interpretation	c.5972G>A (p.Arg1991Gln) in SCN5A (NM_198056.2) Invitae classifies this variant as as a variant of unknown significance. Given the lack of case data, presence in ethnically matched controls, and presence in a case with another very likely pathogenic variant, we consider this variant to be a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in a patient with DCM and a very likely pathogenic LMNA variant. Testing was done by Invitae. The variant has not been reported in a case of cardiomyopathy, but has been seen in published control populations that are ethnically matched to our patient: 1/1300 people (Kapa 2007, Kapplinger 2010) and 1/96 Kenyan people by the 1000 Genomes Project (dbSNP rs199473336). There is no variation at codon 1991 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/7/2016). The mean coverage at that site in ExAC is 70x and the median coverage is 80x, with ~90% of people having 25x coverage.