ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4931G>A (p.Arg1644His) (rs28937316)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183090 SCV000235500 pathogenic not provided 2021-01-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Located near the cytoplasmic end of the S4 segment of domain IV; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Electrophysiological studies in both Xenopus oocytes and mammalian cell lines have shown that R1644H alters the functional properties of the SCN5A channel (Dumaine et al., 1996; Wang et al., 1996); Reported in ClinVar (ClinVar Variant ID#; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 14753626, 10508990, 25904541, 18849657, 26669661, 28721524, 31983221, 8620612, 8917568, 15840476, 15051636, 19841300, 10973849, 15121794, 11273715, 8541846, 26803770, 28220464, 25661095, 28341781, 28412158, 25294783, 29691127, 28573431, 28265756, 28150151, 19026623, 29766885, 31737537, 32383558)
Blueprint Genetics RCV000009963 SCV000264213 pathogenic Long QT syndrome 3 2015-05-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000246905 SCV000319611 pathogenic Cardiovascular phenotype 2019-11-27 criteria provided, single submitter clinical testing The p.R1644H pathogenic mutation (also known as c.4931G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4931. The arginine at codon 1644 is replaced by histidine. This mutation was originally detected in a mother and son affected with long QT syndrome (LQTS) in one family (Wang Q et al. Hum Mol Genet. 1995;4(9):1603-7). Other studies demonstrated disruption of inactivation in channels expressed in a human cell line and in Xenopus oocytes; p.R1644H showed sustained inward current predicted to account for the long QT defect, but findings suggested p.R1644H may be less severe than other alterations studied (Dumaine R et al. Circ Res. 1996;78(5):916-24; Wang DW et al. Proc Natl Acad Sci U.S.A. 1996;93(23):13200-5). In a study of compound mutations as a common cause of severe LQTS, p.R1644H was detected in the father and brother of a child with sudden death who also had a variant in the KCNE1 gene (Westenskow P et al. Circulation. 2004;109(15):1834-41). In a study of individuals with Brugada syndrome, another alteration of the same codon, p.R1644C (c.4930C>T), was reported in one individual and resulted in functionally abnormal protein (Frustaci A et al. Circulation. 2005;112(24):3680-7). Based on the supporting evidence, p.R1644H is interpreted as a disease-causing mutation.
Invitae RCV000472863 SCV000545012 pathogenic Brugada syndrome 2020-03-03 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.
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
OMIM RCV000009963 SCV000030184 pathogenic Long QT syndrome 3 1995-03-10 no assertion criteria provided literature only
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.
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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