3-38551495-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000335.5(SCN5A):c.4874G>A(p.Arg1625His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1625P) has been classified as Pathogenic.
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN5A | NM_001099404.2 | c.4877G>A | p.Arg1626His | missense_variant | Exon 28 of 28 | ENST00000413689.6 | NP_001092874.1 | |
| SCN5A | NM_000335.5 | c.4874G>A | p.Arg1625His | missense_variant | Exon 28 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.4877G>A | p.Arg1626His | missense_variant | Exon 28 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
| SCN5A | ENST00000423572.7 | c.4874G>A | p.Arg1625His | missense_variant | Exon 28 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152024Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251192Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135764
GnomAD4 exome AF: 0.0000575 AC: 84AN: 1461752Hom.: 0 Cov.: 35 AF XY: 0.0000454 AC XY: 33AN XY: 727160
GnomAD4 genome 0.0000263 AC: 4AN: 152024Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74246
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1626 of the SCN5A protein (p.Arg1626His). This variant is present in population databases (rs199473283, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 18752142, 19716085, 22685113, 25904541, 26159999, 31983221). ClinVar contains an entry for this variant (Variation ID: 67934). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (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. -
The SCN5A c.4877G>A; p.Arg1626His variant is reported in individuals with Romano Ward syndrome, Brugada syndrome, dilated cardiomyopathy, or early-onset lone atrial fibrillation (Berge 2008, eMERGE Consortium 2019, Mazzarotto 2020, Olesen 2012). It is also reported by multiple laboratories in the ClinVar database (Variation ID: 67934)and is found in the general population with an overall allele frequency of 0.004% (12/282,654 alleles) in the Genome Aggregation Database (v2.1.1). This variant was reported in one individual with a corrected QT interval not significantly different than individuals without this variant (Ghouse 2015). However, functional analyses of the variant protein show this variant shifts the steady-state activation and inactivation of the SCN5A protein channel, consistent with a gain of function (Olesen 2012). Other variants at this codon (Arg1626Cys, Arg1626Pro) have also been reported in individuals affected with cardiac disease (Banderali 2010, Baruteau 2018, Priori 2000, Ruan 2007). Based on available information, the p.Arg1626His variant is considered to be likely pathogenic. References: Banderali U et al. Impaired stretch modulation in potentially lethal cardiac sodium channel mutants. Channels (Austin). 2010 Jan-Feb;4(1):12-21. Baruteau AE et al. SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups. Eur Heart J. 2018 Aug 14;39(31):2879-2887. Berge KE et al. Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers. Scand J Clin Lab Invest. 2008;68(5):362-8. eMERGE Consortium. Electronic address: agibbs@bcm.edu; eMERGE Consortium. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. Am J Hum Genet. 2019 Sep 5;105(3):588-605. Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020 Feb 4;141(5):387-398. Olesen MS et al. High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation. Circ Cardiovasc Genet. 2012 Aug 1;5(4):450-9. Priori SG et al. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000 Aug 29;102(9):945-7. Ruan Y et al. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation. 2007 Sep 4;116(10):1137-44. -
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 inact -
Identified in a patient with DCM in published literature (PMID: 31983221); Published functional studies demonstrate a gain-of-function effect as the R1626H variant 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 (PMID: 22685113); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22581653, 19716085, 22685113, 24144883, 30609406, 37652022, 35535697, 18752142, 31447099, 33087929, 31357904, 36013246, 26159999, 31983221) -
Long QT syndrome 3 Pathogenic:2
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Cardiovascular phenotype Pathogenic:1
The p.R1626H variant (also known as c.4877G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4877. The arginine at codon 1626 is replaced by histidine, an amino acid with highly similar properties, and is located in the transmembrane DIV-S4 region. This variant has been reported in an individual with early onset lone atrial fibrillation and has been detected in a dilated cardiomyopathy cohort (Olesen MS, Circ Cardiovasc Genet 2012 Aug; 5(4):450-9; Mazzarotto F et al. Circulation. 2020 02;141(5):387-398). In studies of long QT syndrome clinical genetic testing, this alteration was reported in two patients; however, clinical details were limited (Berge KE et al. Scand. J. Clin. Lab. Invest. 2008; 68(5):362-8; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). In vitro studies suggest this variant alters SCN5A channel function (Olesen MS, Circ Cardiovasc Genet 2012 Aug; 5(4):450-9), and internal structural analysis indicates that this variant disrupts a well known arginine characteristic of the voltage sensing region of voltage-gated ion channels. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not specified Uncertain:1
Variant summary: SCN5A c.4877G>A (p.Arg1626His) results in a non-conservative amino acid change located in the Voltage-gated potassium channels. Chain C domain (IPR027359) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251192 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SCN5A causing Brugada Syndrome (4e-05 vs 0.00017), allowing no conclusion about variant significance. c.4877G>A has been reported in the literature in individuals affected with Long QT Syndrome, Atrial Fibrillation or Dilated Cardiomyopathy (Berge_2008, Kapplinger_2009, Olesen_2012, Kapplinger_2015, Ghouse_2015, Mazzarotto_2020, McGurk_2023). These reports do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affects SCN5A function (Olesen_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18752142, 26159999, 25904541, 19716085, 31983221, 37652022, 22685113). ClinVar contains an entry for this variant (Variation ID: 67934). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Cardiac arrhythmia Uncertain:1
This missense variant replaces arginine with histidine at codon 1626 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). A functional study has shown that this variant causes defects in channel function including positive voltage shift of steady-state activation, a negative voltage shift of steady-state inactivation, a decreased onset of fast inactivation, and moderately increased sustained current (PMID: 22685113), while another study has shown that this variant has no impact on channel function (PMID: 31928070). This variant has been reported in two individuals referred for long QT syndrome genetic testing (PMID: 18752142, 19716085) and in an individual affected with early-onset lone atrial fibrillation and flecainide-induced prolonged QT interval (PMID: 22685113, 24144883). This variant has also been reported in an individual with normal QTc interval from a population-based cohort of participants undergoing whole exome sequencing (PMID: 26159999). This variant has been identified in 12/282564 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. -
Congenital long QT syndrome Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at