ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5126C>T (p.Ser1709Leu) (rs137854604)

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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 RCV000246596 SCV000319116 likely pathogenic Cardiovascular phenotype 2013-10-01 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058743 SCV000090263 not provided Ventricular fibrillation no assertion provided literature only This variant has been reported as associated with Ventricular Fibrillation, idiopathic in the following publications (PMID:10940383;PMID:11827685;PMID:17141278;PMID:22247482). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000183102 SCV000235512 pathogenic not provided 2018-08-13 criteria provided, single submitter clinical testing The S1710L variant in the SCN5A gene has been reported in multiple unrelated patients with symptoms including type 1 Brugada syndrome ECG, idiopathic ventricular fibrillation, vasovagal syndrome, and a family history of sudden cardiac death (Shin D et al., 2007; Akai J et al., 2000; Lee et al., 2014). S1710L has also been observed in multiple unrelated individuals tested for Brugada syndrome at GeneDx. S1710L is located in the highly conserved pore-forming linker between segments 5 and 6 in transmembrane domain 4. Functional studies demonstrate that S1710L channels have abnormal biophysical properties, which may result in fast inactivation dysfunction of the sodium channel (Akai J et al., 2000; Shirai N et al., 2002). The S1710L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). S1710L results in a non-conservative amino acid substitution of a polar Serine with a non-polar Leucine. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S1710L as a pathogenic variant.
Invitae RCV000531013 SCV000637172 likely pathogenic Brugada syndrome 2018-05-16 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1710 of the SCN5A protein (p.Ser1710Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs137854604, ExAC 0.009%). This variant has been reported in individuals affected with Brugada syndrome, idiopathic ventricular fibrillation, progressive familial heart block type I, sick sinus syndrome and paroxysmal familial ventricular fibrillation (PMID: 19026623, 14961552, 25326637, 10940383, 22247482, 26798387, 23139254). ClinVar contains an entry for this variant (Variation ID: 9383). This variant identified in the SCN5A gene is located in the transmembrane spanning DIV-S5/S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. Experimental studies have shown that this missense disrupts this sodium ion channel function causing accelerated current decay and onset of fast activation as well as enhanced slow inactivation (PMID: 10940383). In summary, this variant is a missense change that is found in individuals affected with disease and it has been shown experimentally to disrupt protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000009981 SCV000030202 pathogenic Paroxysmal familial ventricular fibrillation 1 2000-08-11 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183102 SCV000280476 likely pathogenic not provided 2014-01-14 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1710Leu (S1710L; c.5129 C>T) in the SCN5A gene This variant has been previously observed in five unrelated cases of Brugada syndrome (including one case of idiopathic VF without a strict Brugada diagnosis). No published segregation data is available, but good in-vitro functional data is available. With our 2 cases (both have Mexican ancestry), this makes 7 families. Akai et al. (2000) first reported the variant in a Japanese patient with idiopathic ventricular fibrillation, a history of recurrent syncope, and sudden death in a paternal uncle and paternal grandfather, but no type 1 Brugada pattern on EKG. Shin et al. (2007) reported the variant in a male Korean patient with a type 1 Brugada syndrome pattern on EKG that was unmasked by flecainide and a family history of sudden cardiac death. The testing laboratory reports that Ser1710Leu has also been seen in three additional unrelated individuals tested for Brugada syndrome at their lab (as of January 2014). Functional data is available. The SCN5A gene produces the cardiac sodium channel alpha subunit, and Ser1710 is located in the highly conserved pore-forming linker between segments 5 and 6 in transmembrane domain 4 (Akai et al. 2000; Shin et al. 2007). Functional studies show that Ser1710Leu mutant channels have altered biophysical properties, which may result in diminished sodium current into the myocyte. Akai et al. (2000) and Shirai et al. (2002) showed that mutant channels expressed in human embryonic kidney cells show faster inactivation and current decay, a large hyperpolarizing shift in the voltage-dependent threshold for steady-state inactivation, a positive shift in the voltage-dependent threshold for channel activation, and delayed recovery from inactivation. Variants at nearby residues (within 10 amino acids to either side) have been associated with Brugada syndrome, suggesting the functional importance of this region of the protein. These include Thr1709Arg, Thr1709Met, Thr1709del, Gly1712Ser, Asp1714Gly (inherited arrhythmias database: Molecular Cardiology Laboratories of IRCCS Fondazione Salvatore Maugeri; GeneDx report of HGMD variants). Ser1710Leu is a nonconservative amino acid change from a polar Serine to a nonpolar Leucine. The Serine at codon 1710 is completely conserved across 39 vertebrate species examined. Surrounding residues are also very highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be "probably damaging" (with a maximum score of 1). In total the variant has not been seen in ~6850 individuals from published reports and publicly available population datasets. There is no variation at residue 1710 listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of June 27, 2012. The variant was not observed in published controls: Akai et al. (2000) did not find Ser1710Leu in 150 (Japanese?) controls. Shin et al. (2007) did not detect it in 200 Korean controls. GeneDx did not report controls.
UCLA Clinical Genomics Center, UCLA RCV000197520 SCV000255460 likely pathogenic Brugada syndrome 1 2013-09-10 criteria provided, single submitter clinical testing

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