ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4877G>A (p.Arg1626His) (rs199473283)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183089 SCV000235499 pathogenic not provided 2017-01-16 criteria provided, single submitter clinical testing The R1626H pathogenic variant has been previously reported in association with LQTS (Berge et al., 2008; Kapplinger et al., 2009), and early-onset lone atrial fibrillation (Olesen et al., 2012; Olesen et al., 2014). Berge et al. (2008) and Kapplinger et al. (2009) initially reported R1626H in two unrelated individuals referred for LQTS genetic testing. The R1626H variant was also reported in one 37-year-old Danish male with early-onset lone paroxysmal atrial fibrillation, a flecainide-induced prolonged QT interval, and a negative family history of atrial fibrillation (Olesen et al., 2012; Olesen et al., 2014). More recently, this variant was identified in one individual from a population-based Danish cohort of 869 individuals who underwent exome sequencing; this individual's corrected QT interval was not found to be significantly different from individuals without the R1626H variant (Ghouse et al., 2015). Additional clinical and family history information was not available for any of the individuals identified in the studies mentioned above. The R1626H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although R1626H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs within the voltage-sensor region of the S4 segment of domain IV at a position that is conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, patch clamp analysis in HEK293 cells demonstrated R1626H mutant channel causes a positive voltage shift in steady-state activation, a negative voltage shift in steady state inactivation, decreased fast inactivation, and a two- to three-fold increased sustained sodium current, compared to wild-type channel, consistent with a gain-of-function effect (Olesen et al., 2012).
Ambry Genetics RCV000252940 SCV000320666 likely pathogenic Cardiovascular phenotype 2016-06-13 criteria provided, single submitter clinical testing Structural Evidence;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Illumina Clinical Services Laboratory,Illumina RCV000779405 SCV000916017 uncertain significance Long QT syndrome 3 2017-04-28 criteria provided, single submitter clinical testing The SCN5A c.4877G>A (p.Arg1626His) missense variant has been reported in two individuals with long QT syndrome (Berge et al. 2008; Kapplinger et al. 2009). The p.Arg1626His variant has also been found in one individual with lone atrial fibrillation (Olesen et al. 2012). The p.Arg1626His variant was absent from 94 healthy controls and is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using expression of p.Arg1626His protein in mammalian HEK293 cells, followed by whole cell patch-clamp analysis revealed a two- to three-fold increased sustained sodium current, consistent with a gain-of-function effect (Olesen et al. 2012). Based on the evidence, the p.Arg1626His variant is classified as a variant of unknown significance but suspicious for pathogenicity for long QT syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000779405 SCV000993582 likely pathogenic Long QT syndrome 3 2019-01-04 criteria provided, single submitter research
Invitae RCV001036426 SCV001199790 uncertain significance Brugada syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1626 of the SCN5A protein (p.Arg1626His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473283, ExAC 0.02%). This variant has been reported in the literature in several individuals referred for long QT testing (PMID: 18752142, 26159999, 25904541, 19716085), and in an individual affected with lone atrial fibrillation (PMID: 22685113). ClinVar contains an entry for this variant (Variation ID: 67934). Experimental studies have shown that this missense change shifts the steady-state activation and inactivation of the SCN5A protein channel (PMID: 22685113). 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 RCV001184209 SCV001350149 uncertain significance Arrhythmia 2019-12-09 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058718 SCV000090238 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:18752142;PMID:19716085;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183089 SCV000924942 uncertain significance not provided 2016-08-22 no assertion criteria provided provider interpretation p.Arg1626His (c.4877G>A) in SCN5A (NM_198056) Seen in a patient in our center with no signs of long QT or Brugada. Variant was identified on secondary search when patient had clinical exome sequencing for a neurological indication. Given the weak case data and the allele frequency in ExAC we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). I discussed the variant with our clinical genome service as well as another clinical lab we often use for cardiac genetic testing and both agreed it is a variant of uncertain significance nothing the allele frequency in ExAC is too high. The variant has been seen in more than two individuals sent to a clinical laboratory for long QT genetic testing (with no phenotypic data available) and an individual with early-onset atrial fibrillation and a normal QTc that lengthened with Flecainide provocation. It has been seen in multiple individuals in the general population; ECG on one of those individuals showed a normal QT interval. There is no segregation data available. Berge et al (2008) observed the variant in 1 of 169 individuals referred for autosomal dominant long QT syndrome genetic testing. They do not report ancestry, however the cases were seen as part of regular clinical care at a laboratory in Norway. The variant was reported in 1 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Ancestry was not reported. Those cases likely overlap with the data in Kapa et al (2009), Giudicessi et al (2012) and Kapplinger et al (2015) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Olesen et al (2012) observed the variant in 1 of 192 people with lone early-onset atrial fibrillation (onset 16 to 39yo). Ancestry was "Danish/white". The patient had a normal QTc of 443 ms, however, on Flecainide testing the QTc lengthened to 495 ms. The same group then looked for variants published in association with long QT syndrome in a Danish population sample (Ghouse et al 2015). They observed this variant in 1 of 869 individuals and that individual had a normal QTc. GeneDx notes that they have observed the variant in multiple people tested in their laboratory but they do not provide phenotypic details. Per the lab report, in silico analysis with PolyPhen-2 and SIFT predicts the variant to be probably damaging. The arginine at codon 1626 is conserved across species and paralogues. Per ClinVar and cardiodb.org, other variants have been reported in association with disease at this codon (Arg1626Pro) and nearby codons (Arg1623Gln, Arg1623Leu, Arg1629Gln, Arg1629Gl). p.Arg162Pro is not present in Exac. The only ClinVar entry is from Royal Brompton, as pathogenic. Priori's group observed it in 1/430 individuals with long QT syndrome (Napolitano et al 2005; presumably same case as Priori et al 2000 and Ruan et al 2007) Per paralogue annotation by cardiodb.org, variants at the corresponding codon in several genes have been reported in association with disease (SCN1A, SCN4A, CACNA1S, CACNA1A, SCN2A). The variant occurs in the last (most C terminal) transmembrane domain. When comparing variants in cases to controls, Ackerman's group assessed that variants in the transmembrane domains have an 88% likelihood of being in seen in a case, not a control (Kapa et al 2009). Olesen et al (2012) studied the variant in vitro and reported a gain of function effect with positive voltage shift in steady-state activation, negative voltage shift in steady-state inactivation, decreased fast inactivation, 2-3 fold increased sustained sodium current. The variant was reported online in 8 of 60631 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Aug 15, 2016). Specifically, the variant was observed in 7 of 33350 non-Finnish Europeans (allele frequency 0.01%) and 1 of 3307 Finish Europeans (allele frequency 0.015%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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