ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4928G>A (p.Arg1643His) (rs28937316)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246905 SCV000319611 pathogenic Cardiovascular phenotype 2015-03-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Other strong data supporting pathogenic classification
Blueprint Genetics RCV000009963 SCV000264213 pathogenic Long QT syndrome 3 2015-05-13 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058726 SCV000090246 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:8541846;PMID:10973849;PMID:15051636;PMID:15840476;PMID:19841300;PMID:8620612;PMID:8917568). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000009963 SCV000805136 pathogenic Long QT syndrome 3 2018-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000183090 SCV000235500 pathogenic not provided 2017-02-10 criteria provided, single submitter clinical testing The R1644H pathogenic variant in the SCN5A gene has been published previously in multiple individuals with LQTS (Wang et al., 1995; Splawski et al., 2000; Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2015). This variant has also been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000264213.1; Landrum et al., 2016). In addition, R1644H was not present in more than 3,800 reference alleles from various ethnic groups, indicating it is not a common benign polymorphism (Splawski et al., 2000; Tester et al., 2005; Kapa et al., 2009). Similarly, the NHLBI Exome Sequencing Project reports R1644H was not observed in approximately 6,500 individuals from European and African American backgrounds. In vitro functional studies of R1644H have demonstrated increased persistent sodium currents compared to the wild-type channels (Dumaine et al., 1996; Wang et al., 1996). Finally, this residue is located in the S4 voltage sensor transmembrane helix of DIV. In summary, R1644H in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000472863 SCV000545012 pathogenic Brugada syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1644 of the SCN5A protein (p.Arg1644His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with long QT syndrome (PMID: 8541846, 10973849, 19026623, 19841300). ClinVar contains an entry for this variant (Variation ID: 9369). Experimental studies have shown that this missense change causes a persistent inward current indicating continued channel gating that is not voltage dependent (PMID: 8620612, 8917568). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009963 SCV000030184 pathogenic Long QT syndrome 3 1995-03-10 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183090 SCV000924940 likely pathogenic not provided 2017-09-22 no assertion criteria provided provider interpretation SCN5A Arg1644His c.4931G>A in exon 28, (NM_198056.2, ENST00000303395) hg19 chr3-38592932-C-T SCICD Classification: Likely pathogenic, based on adequate case data, absence in population datasets, and location in region enriched for disease variants. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data: -1 case of LQTS in our center - at least 3 cases of LQTS published (below) - 3 cases "referred for LQTS genetic testing", phenotypes unavailable (below) LQTS cases in the literature: Wang et al., 1995 (PMID 8541846) - segregated in a mother and son with long QT (recruited in Europe, North America, overlapping authors with Splawski et al so may be redundant) Splawski et al., 2000 (PMID 10973849)- seen in 2 families with long QT (recruited in Europe, North America, overlapping authors with Wang et al so may be redundant) Millat et al., 2009 (PMID 19026623) - seen in 1 male with long QT (study done in France, no overlap with other authors, recruitment location not noted). Cases "referred for LQTS genetic testing": Tester et al., 2005 (PMID 15840476) - Seen in 2 unrelated people referred for long QT testing, Ackerman's long QT testing series (tested in his lab), probably not overlapping with Kapplinger et al. Kapplinger et al., 2009 - seen in 1 patient referred for long QT testing at Familion. Those cases likely overlap with the data in Kapa et al (2009) 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). Segregation data: segregated with disease in 2 family members (Wang et al., 1995) Functional data: This residue is located in the S4 voltage sensor transmembrane helix of domain IV of the protein. These region is enriched for variants seen in cases vs controls (https://www.cardioclassifier.org/Classifier). Dumaine et al., 1996 (PMID 8620612): heterologous expression in Xenopus oocytes showed inactivation resistance Wang et al., 1996 (PMID 8917568) - heterologous expression in human HEK 293 tsA-201 cells showed showed sustained inward current and non-zero variance, indicating continued channel gating, at times later than 20 msec. Paralogue data from cardiodb: Several variants at position 1644 in paralogous proteins have been reported to be disease causing. A corresponding Arginine to Histidine substitution was reported to cause cryptogenic focal epilepsy in the SCN1A gene (one de novo case). Arginine to Cysteine substitutions at the corresponding amino acids have also been reported in SCN1A (to cause generalized epilepsy with febrile seizures) and CACNA1A (episodic ataxia 2). Conservation data: Per the lab report, The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. There is no variation at codon 1644 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is mean 32.9x, median 32x, and 93.75% of samples have >20x coverage; in exomes it is mean 96.8x, median 100x, and 100% of samples have >20x coverage.

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