Submissions for variant NM_000335.5(SCN5A):c.5620_5622dup (p.Met1874dup)

dbSNP: rs1474459822

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624731	SCV000740420	likely pathogenic	not provided	2016-11-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002343173	SCV002648468	uncertain significance	Cardiovascular phenotype	2022-08-26	criteria provided, single submitter	clinical testing	The c.5623_5625dupATG variant (also known as p.M1875dup), located in coding exon 27 of the SCN5A gene, results from an in-frame duplication of ATG at nucleotide positions 5623 to 5625. This results in the duplication of an extra methionine residue between codons 1875 and 1876. This variant has been previously detected in an individual reported to have Brugada syndrome (Hsueh CH et al. J Biomed Sci, 2009 Feb;16:23). In vitro studies by one group suggest this variant may have some impact on protein function (Hsueh CH et al. J Biomed Sci, 2009 Feb;16:23). This amino acid region is highly conserved in available vertebrate species and the impacted region is critical for protein function (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetics and Molecular Pathology, SA Pathology	RCV002466547	SCV002761463	likely pathogenic	Brugada syndrome 1	2021-03-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002746	SCV004828092	uncertain significance	Cardiac arrhythmia	2023-08-28	criteria provided, single submitter	clinical testing	This variant causes a duplication of methionine at codon 1875 of the SCN5A protein. This variant is also known as p.Met1874dup based on a different transcript NM_000335.5. This variant is found within the highly conserved C-terminal region (a.a. 1773-2016). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant traffics to the cell surface similarly to wildtype channels, but has altered electrophysiological properties (PMID: 19272188). This variant has been reported in an individual affected with Brugada syndrome (PMID: 19272188). This variant has been identified in 2/280672 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002466547	SCV005399307	likely pathogenic	Brugada syndrome 1	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. PTCs cause a loss of function mechanism, while missense are both loss and gain of function (OMIM, PMID: 29806494). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Recessive disease is caused by loss of function variants, while dominant disease is both loss and gain of function (OMIM, PMID: 29806494). (N) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation (exon 28). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. (N) 0600 - Variant is located in an annotated domain or motif, (5th helice of the carboxyl-terminal region; PMID: 19272188). (N) 0705 - No comparable variants have previous evidence for pathogenicity. A missense variant are this same residue (p.Met1875Thr) has been commonly reported as a pathogenic variant causing atrial fibrillation (ClinVar). (N) 0803 - Low previous evidence of pathogenicity in two unrelated individuals, one with Brugada syndrome (ClinVar, PMID: 19272188). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected cells displayed mostly loss of function effects on steady state channel activation and inactivation and recovery (PMID: 19272188). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign