ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5474G>A (p.Arg1825His) (rs137854610)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619902 SCV000737585 uncertain significance Cardiovascular phenotype 2016-06-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148848 SCV000190591 uncertain significance SUDDEN INFANT DEATH SYNDROME 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058786 SCV000090306 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:11710892;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000766811 SCV000235534 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The R1826H variant has been previously reported in a Caucasian male who died at one month of age due to an undetermined cause of death (Ackerman et al., 2001). Kapplinger et al. (2009) also reported this variant in two individuals from a cohort of 2500 participants referred for LQTS genetic testing. In both these studies, additional clinical details and segregation studies were not described. This variant has also been reported as an incidental finding in a Chinese individual from a cohort of individuals undergoing whole exome or genome sequencing (Jamuar et al., 2016), although a follow-up cardiac evaluation was not reported. The R1826H variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).While R1826H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies in HEK293 cells showed that SCN5A channels harboring R1826H resulted in a slower decay in sodium current and a 2- to 3-fold increase in late sodium current, suggesting this variant causes a gain-of-function effect (Ackerman et al., 2001). However, the causative role of this variant in human disease still remains to be determined and additional functional evidence and segregation studies are needed to further clarify its pathogenicity. Additionally, although a missense variant at the same residue (R1826C) has been reported in association with atrial fibrillation (Darbar et al., 2008), this clinical significance of this variant also remains to be definitively determined. Finally, R1826H is also classified as a variant of uncertain significance in ClinVar by a different clinical laboratory (ClinVar SCV000204509.3; Landrum et al., 2016).
Invitae RCV000550842 SCV000637182 uncertain significance Brugada syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1826 of the SCN5A protein (p.Arg1826His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs137854610, ExAC 0.01%). This variant has been observed in individuals who suffered sudden infant death syndrome (PMID: 11710892, 30079003) and in individuals referred for long QT testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 9389). This variant has been reported to affect SCN5A protein function (PMID: 11710892). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154827 SCV000204509 uncertain significance not specified 2018-02-27 criteria provided, single submitter clinical testing The p.Arg1826His variant in SCN5A has been previously reported in 1 infant with SIDS, 2 individuals with LQTS, and 1 individual with infantile-onset of HCM (Ack erman 2001, Kapplinger 2009, LMM data). It has also been identified in 7/24022 A frican chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs137854610) and reported in ClinVar (Variation ID 9389). Functional studies have shown that the Arg1826His variant impacts protein funct ion (Ackerman 2001). However, this in vitro assay may not accurately represent b iological function. Additional computational prediction tools and conservation a nalysis suggest that this variant may impact the protein, though this informatio n is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg1826His variant is uncertain. ACMG/AMP Criteria applied : PP3; PS4_Supporting; PS3_Supporting.
OMIM RCV000009987 SCV000030208 pathogenic Long QT syndrome 3 2001-11-14 no assertion criteria provided literature only

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