ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5347G>A (p.Glu1783Lys) (rs137854601)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245905 SCV000319877 pathogenic Cardiovascular phenotype 2016-10-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Strong segregation with disease (lod >3 = >10 meioses)
Blueprint Genetics RCV000208193 SCV000264215 pathogenic Brugada syndrome 2015-07-22 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058773 SCV000090293 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:10377081;PMID:10961955;PMID:10973849;PMID:12877697;PMID:15840476;PMID:16379539;PMID:18451998;PMID:19716085;PMID:19841300;PMID:10727653). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000183117 SCV000610392 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000009972 SCV000536870 pathogenic Long QT syndrome 3 2016-02-25 no assertion criteria provided research
GeneDx RCV000183117 SCV000235527 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The E1784K pathogenic variant in the SCN5A gene has been published previously in several unrelated patients with LQTS and Brugada syndrome, and this variant was not seen in more than 2,600 normal control alleles (Wei et al., 1999; Splawski et al., 2000; Priori et al., 2000; Tester et al., 2005; Shim et al., 2005; Makita et al., 2008; Kapplinger et al., 2009; Nakajima et al., 2011). In addition, E1784K was not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). Makita et al. (2008) and Nakajima et al. (2011) noted carriers of the E1784K variant exhibited ST elevation in addition to prolonged QT intervals, demonstrating a phenotypic overlap between LQTS and Brugada syndrome in some patients with this variant. In addition, the E1784K variant has been shown to co-segregate with features of LQTS or Brugada syndrome in multiple families (Wei et al., 1999; Makita et al., 2008). According to functional studies, mutant channels demonstrate faster current decay and increased persistent current as compared to the normal channels (Priori et al., 2000; Makita et al., 2008). The E1784K variant results in a non-conservative amino acid substitution of a negatively charged glutamic acid with a positively charged lysine at a residue that is conserved across species.
Integrated Genetics/Laboratory Corporation of America RCV000588022 SCV000700038 pathogenic Long QT syndrome 1 2016-05-10 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.5350G>A (p.Glu1784Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 121222 control chromosomes, but has been reported in the literature in numerous affected individuals, including patients with both LQTS and Brugada syndrome. In functional studies, the variant showed a persistent inward sodium current, which has also been previously observed as a functional defect in other LQTS SCN5A mutations (Wei_1999, Deschenes_2000). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000208193 SCV000291817 pathogenic Brugada syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1784 of the SCN5A protein (p.Glu1784Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate in families with long QT syndrome and sick sinus syndrome (PMID: 18451998, 10377081, 24762805). It has also been reported in multiple unrelated individuals affected with long QT syndrome and Brugada syndrome (PMID: 10727653, 21321465, 19841300, 12877697, 10973849, 16379539, 10961955, 18452873, 23631430). ClinVar contains an entry for this variant (Variation ID: 9377). This variant identified in the SCN5A gene is located in the cytoplasmic C-terminal 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 change causes a negative shift in the sodium channel steady-state inactivation with a persistent inward current (PMID: 10377081, 10727653, 18451998). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824758 SCV000711786 pathogenic Brugada syndrome; Congenital long QT syndrome 2016-07-08 criteria provided, single submitter clinical testing The p.Glu1784Lys variant in SCN5A has been previously reported in >20 individual s with prolonged QT intervals, Long QT syndrome (LQTS), and/or Brugada syndrome , including 1 de novo occurrence (Wei 1999, Makita 2008, Deschenes 2000, Nakajim a 2011, Takahashi 2014). Furthermore, the variant segregated with disease in man y affected relatives (LQTS, Brugada syndrome, or prolonged QT intervals; Makita 2008, Wei 1999, Deschenes 2000, Shim 2005, Veltmann 2016). This variant has also been classified by other clinical laboratories as pathogenic in ClinVar (Variat ion ID: 9377) and has been identified in 1/111718 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). In vitr o functional studies provide some evidence that the p.Glu1784Lys variant may imp act protein function (Deschenes 2000, Makita 2008). In summary, this variant mee ts criteria to be classified as pathogenic for LQTS and Brugada syndrome in an a utosomal dominant manner based upon presence in multiple affected individuals, s egregation studies, very low frequency in controls and functional studies. ACMG/ AMP criteria applied: PS4_Strong; PP1_Strong; PS3_Supporting, PM2.
OMIM RCV000009972 SCV000030193 pathogenic Long QT syndrome 3 2008-06-01 no assertion criteria provided literature only
OMIM RCV000009973 SCV000030194 pathogenic Brugada syndrome 1 2008-06-01 no assertion criteria provided literature only
OMIM RCV000009974 SCV000030195 pathogenic Sinus node disease 2008-06-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000009972 SCV000883206 likely pathogenic Long QT syndrome 3 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Likely Pathogenic, for Long QT syndrome 3, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183117 SCV000280478 pathogenic not provided 2015-05-26 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.Glu1784Lys (c.5350G>A) in SCN5A (NM_001099404.1, ENST00000413689) Given the very strong case data, segregation data, and absence in individuals unselected for rare cardiac disease, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 30 unrelated cases of inherited channelopathy, and likely more than 52 cases (not including this patient's family). There is strong segregation data. Of note, the variant has been reported with a range of SCN5A-associated phenotypes including long QT syndrome type 3, Brugada syndrome, and conduction system disease (see Makita et al 2008 for multicenter data on the varied phenotype). Interestingly, the variant appears to be the most frequently identified long QT type 3 variant and the most frequently identified Brugada syndrome variant in a variety of cohorts. Makita et al (2008) report on 44 carriers of this variant across 15 families from multiple centers around the world (many likely overlap with prior reports). Most carriers had evidence of LQT3 (93%), 22% had evidence of Brugada syndrome, and 39% had sinus node dysfunction. All of the patients with evidence of Brugada also had evidence of long QT type 3. Half of the patients with Brugada had sinus node dysfunction. Only 2/44 carriers had no evidence of these three phenotypes, indicating high penetrance in this cohort. Of note, some carriers had evidence of all three phenotypes. Wei et al (1999) reported the variant in a Caucasian family with evidence of long QT syndrome (QTc 464-527 ms in affected relatives), sudden death at 13yo while at rest with native autopsy, sinus bradycardia, prominent unit(s) waves, ventricular ectopy during bradycardic episodes with occasional sinus pauses and one family member with "isoelectric ST segments". The authors are from Vanderbilt. They sequenced select exons of SCN5A in the family. The variant segregated with disease in 4 affected family members, including two first cousins. Priori et al (2000) reported on family with long QT syndrome and this variant. It isn't completely clear from the report, but it appears that three affected members of this family had this variant (QTc 496, 510, 520). A 12yo girl in this family had a resting QTc of 480 ms. With Flecainide provocation her QT shortened to 460 ms and ST segment elevation was provoked. Splawski et al (2000) observed the variant in 2 of 262 unrelated patients with long QT who underwent analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2. Patients were ascertained in Europe and North America (may overlap with reports by Priori's group, the US long QT registry, the international long QT registry). No ancestry, segregation, or individual phenotype data was provided. (Splawski et al 2000). Priori et al (2002) observed this variant in at least one patient with Brugada syndrome from a cohort of 130 unrelated patients with Brugada, presumably recruited in Italy (though that is not clear). Ackerman's group reported 3 unrelated patients with long QT syndrome and this variant Nemec et al 2003). They do not state where subjects were recruited, but all authors are form Mayo so presumably there. It appears that sequencing was done in Ackerman's research lab at Mayo. They note that one patient with this variant had microvoltage T wave alternans at baseline. In a subsequent paper they report an additional case, for a total of 4 (Tester et al 2005). Shim et al (2005) reported on a variant, E1783K, that appears to be the same variant, but with a slightly different number system. They observed it in two infants who underwent genetic testing at their laboratory at Boston University. Both had prolonged QT intervals and family history of sudden death in multiple family members. Behr et al (2008) identified the variant in a sudden death case from their London cohort. The variant was reported in 15 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Tester et al, Nemec et al 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). Nakajima et al (2011) observed the variant in one of 30 Japanese probands with Brugada syndrome. Kapplinger et al (2010) reported 14 patients with this variant in their international compendium of SCN5A Brugada variants, likely overlapping with prior reports. Takahashi et al (2014) observed the variant 14 of 23 children found to have long QT syndrome through a school based ECG screening program in Okinawa, japan. There is only one submission from a clinical lab in ClinVar, Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust. They classify it as pathogenic. The variant occurs in the C terminus, just distal to the D4 transmembrane domain. Wei et al (1999) studied the effects of the variant in vitro and observed a defect in fast inactivation in xenopus oocytes. Makita et al (2008) report a negative shift in the voltage dependence of sodium channel inactivation and an increase in flecainide affinity for resting-state channels. They note these properties have been seen in other variants associated with mixed phenotypes. There is no variation at codon 1784 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of May 26th, 2015). Of note given both the patient's ancestry and the ancestry of some cases, this includes ~4300 East Asian individuals.

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