NM_000335.5(SCN5A):c.5537G>A (p.Arg1846His) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 9, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001753453.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.5537G>A (p.Arg1846His)]

NM_000335.5(SCN5A):c.5537G>A (p.Arg1846His)

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.5537G>A (p.Arg1846His)

HGVS:

NC_000003.12:g.38550832C>T
NG_008934.1:g.103841G>A
NM_000335.5:c.5537G>AMANE SELECT
NM_001099404.2:c.5540G>A
NM_001099405.2:c.5486G>A
NM_001160160.2:c.5441G>A
NM_001160161.2:c.5378G>A
NM_001354701.2:c.5483G>A
NM_198056.3:c.5540G>A
NP_000326.2:p.Arg1846His
NP_001092874.1:p.Arg1847His
NP_001092875.1:p.Arg1829His
NP_001153632.1:p.Arg1814His
NP_001153633.1:p.Arg1793His
NP_001341630.1:p.Arg1828His
NP_932173.1:p.Arg1847His
NP_932173.1:p.Arg1847His
LRG_289t1:c.5540G>A
LRG_289:g.103841G>A
LRG_289p1:p.Arg1847His
NC_000003.11:g.38592323C>T
NM_198056.2:c.5540G>A
c.5540G>A

Protein change:

R1793H

Links:

dbSNP: rs369058100

NCBI 1000 Genomes Browser:

rs369058100

Molecular consequence:

NM_000335.5:c.5537G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5540G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5486G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5441G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5378G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5483G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5540G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000760245	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 25, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23321620, 28492532
SCV001985372	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 9, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000760245

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 25, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001985372

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 9, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification.

Sommariva E, Pappone C, Martinelli Boneschi F, Di Resta C, Rosaria Carbone M, Salvi E, Vergara P, Sala S, Cusi D, Ferrari M, Benedetti S.

Eur J Hum Genet. 2013 Sep;21(9):911-7. doi: 10.1038/ejhg.2012.289. Epub 2013 Jan 16.

PubMed [citation]

PMID:: 23321620
PMCID:: PMC3746265

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000760245.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 48309). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 23321620). This variant is present in population databases (rs369058100, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1847 of the SCN5A protein (p.Arg1847His).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001985372.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed in an individual with Brugada syndrome (PMID: 23321620); Not observed at significant frequency in large population cohorts (gnomAD); 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: 30203441, 30662450, 23321620)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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