Submissions for variant NM_000335.5(SCN5A):c.5537G>A (p.Arg1846His)

gnomAD frequency: 0.00001  dbSNP: rs369058100

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041629	SCV000065325	uncertain significance	not specified	2019-02-06	criteria provided, single submitter	clinical testing	This variant has been identified in 1 individual with HCM and segregated with disease in 1 family member (LMM data). This variant has also been reported in an individual affected with Brugada syndrome (Sommariva 2013). It is present in ClinVar (ID: 48309). It has also been detected in 1/10352 Ashkenazi Jewish chromosomes in gnomAD.
Center for Human Genetics, University of Leuven	RCV000498301	SCV000579531	uncertain significance	Brugada syndrome 1	2017-02-09	criteria provided, single submitter	clinical testing	ACMG score unknown significance
Labcorp Genetics (formerly Invitae), Labcorp	RCV001753453	SCV000760245	uncertain significance	not provided	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1847 of the SCN5A protein (p.Arg1847His). This variant is present in population databases (rs369058100, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 23321620). ClinVar contains an entry for this variant (Variation ID: 48309). 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	RCV001841612	SCV001357292	uncertain significance	Cardiac arrhythmia	2018-12-11	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal region this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 23321620). This variant has also been identified in 3/277036 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx	RCV001753453	SCV001985372	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	Observed in an individual with Brugada syndrome (PMID: 23321620); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30203441, 30662450, 23321620)
Ambry Genetics	RCV004018916	SCV004944533	uncertain significance	Cardiovascular phenotype	2022-09-15	criteria provided, single submitter	clinical testing	The c.5540G>A (p.R1847H) 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 5540, causing the arginine (R) at amino acid position 1847 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001841612	SCV005428215	uncertain significance	Cardiac arrhythmia	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1847 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved C-terminal region (a.a. 1773-2016). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with Brugada syndrome (PMID: 23321620, 29255176) and in one individual affected with hypertrophic cardiomyopathy (ClinVar SCV000065325.7). This variant has been identified in 3/280554 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.