NM_000335.5(SCN5A):c.4928G>A (p.Arg1643His) AND not provided

Clinical significance:Pathogenic (Last evaluated: Jan 6, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000183090.5

Allele description [Variation Report for NM_000335.5(SCN5A):c.4928G>A (p.Arg1643His)]

NM_000335.5(SCN5A):c.4928G>A (p.Arg1643His)

Gene:
SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000335.5(SCN5A):c.4928G>A (p.Arg1643His)
Other names:
p.R1644H:CGC>CAC
HGVS:
  • NC_000003.12:g.38551441C>T
  • NG_008934.1:g.103232G>A
  • NM_000335.5:c.4928G>AMANE SELECT
  • NM_001099404.2:c.4931G>A
  • NM_001099405.2:c.4877G>A
  • NM_001160160.2:c.4832G>A
  • NM_001160161.2:c.4769G>A
  • NM_001354701.2:c.4874G>A
  • NM_198056.2:c.4931G>A
  • NM_198056.3:c.4931G>A
  • NP_000326.2:p.Arg1643His
  • NP_001092874.1:p.Arg1644His
  • NP_001092875.1:p.Arg1626His
  • NP_001153632.1:p.Arg1611His
  • NP_001153633.1:p.Arg1590His
  • NP_001341630.1:p.Arg1625His
  • NP_932173.1:p.Arg1644His
  • NP_932173.1:p.Arg1644His
  • LRG_289t1:c.4931G>A
  • LRG_289:g.103232G>A
  • LRG_289p1:p.Arg1644His
  • NC_000003.11:g.38592932C>T
  • Q14524:p.Arg1644His
Protein change:
R1590H; ARG1644HIS
Links:
UniProtKB: Q14524#VAR_001579; OMIM: 600163.0002; dbSNP: rs28937316
NCBI 1000 Genomes Browser:
rs28937316
Molecular consequence:
  • NM_000335.5:c.4928G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.4931G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.4877G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.4832G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.4769G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.4874G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.2:c.4931G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.4931G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000235500GeneDxcriteria provided, single submitter
Pathogenic
(Jan 6, 2021)
germlineclinical testing

Citation Link,

SCV000924940Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Sep 22, 2017)
germlineprovider interpretation

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedprovider interpretation
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000235500.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924940.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedprovider interpretationnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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