Submissions for variant NM_000335.5(SCN5A):c.3803A>G (p.Asn1268Ser)

dbSNP: rs761274563

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001089973	SCV001245001	likely pathogenic	Dilated cardiomyopathy 1E	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss- or gain of function mechanism (PMID: 29798782). However, some variants simultaneously result in both a loss- and gain of function effect, and have been observed in patients with LQTS, Brugada syndrome or SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (MIM#614022) (PMID: 29806494, PMID: 19167345, PMID: 26798387). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited, however SSS can be caused by recessive variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in a placental mammal. (I) 0600 - Variant is located in the annotated DIII-S2/S3 region of an ion transporter domain (NCBI, PMID: 22840528). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported several times as a VUS (ClinVar). However, it has also been observed in an individual with Brugada syndrome and regarded as putative pathogenic (PMID: 22840528), and was observed six times in a cohort of LQTS patients (PMID: 27566755). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by quad analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Illumina Laboratory Services, Illumina	RCV001144754	SCV001305368	uncertain significance	Sick sinus syndrome 1	2017-06-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001144755	SCV001305369	uncertain significance	Long QT syndrome 3	2017-06-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001144756	SCV001305370	uncertain significance	Progressive familial heart block, type 1A	2017-06-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001089973	SCV001305371	uncertain significance	Dilated cardiomyopathy 1E	2017-06-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001150867	SCV001311962	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2017-06-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001150868	SCV001311963	uncertain significance	Brugada syndrome 1	2017-06-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001842609	SCV001349917	uncertain significance	Cardiac arrhythmia	2023-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1269 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 been reported in an individual tested for Brugada syndrome (PMID: 22840528). This variant has been identified in 1/251430 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	RCV001759861	SCV001516536	uncertain significance	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1269 of the SCN5A protein (p.Asn1269Ser). This variant is present in population databases (rs761274563, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features related to Brugada syndrome (PMID: 22840528). ClinVar contains an entry for this variant (Variation ID: 870402). 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.
GeneDx	RCV001759861	SCV001985374	uncertain significance	not provided	2019-11-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in an asymptomatic individual with no family history who has type 1 Brugada syndrome findings on electrocardiogram in published literature (Crotti et al., 2012); This variant is associated with the following publications: (PMID: 22840528, 30662450)
Ambry Genetics	RCV002355108	SCV002620178	uncertain significance	Cardiovascular phenotype	2020-01-03	criteria provided, single submitter	clinical testing	The p.N1269S variant (also known as c.3806A>G), located in coding exon 20 of the SCN5A gene, results from an A to G substitution at nucleotide position 3806. The asparagine at codon 1269 is replaced by serine, an amino acid with highly similar properties, and is located in the DIII-S2/S3 region of the protein. This alteration has been reported in a Brugada syndrome cohort (Crotti L et al. J. Am. Coll. Cardiol., 2012 Oct;60:1410-8). This amino acid position is highly conserved in available vertebrate species; however, serine 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.
All of Us Research Program, National Institutes of Health	RCV001842609	SCV004827766	uncertain significance	Cardiac arrhythmia	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1269 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 been reported in an individual tested for Brugada syndrome (PMID: 22840528). This variant has been identified in 1/251430 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.