NM_000335.5(SCN5A):c.101G>A (p.Arg34His) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 16, 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:: RCV000058383.16

Allele description

NM_000335.5(SCN5A):c.101G>A (p.Arg34His)

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.101G>A (p.Arg34His)

HGVS:

NC_000003.12:g.38633207C>T
NG_008934.1:g.21466G>A
NM_000335.5:c.101G>AMANE SELECT
NM_001099404.2:c.101G>A
NM_001099405.2:c.101G>A
NM_001160160.2:c.101G>A
NM_001160161.2:c.101G>A
NM_001354701.2:c.101G>A
NM_198056.3:c.101G>A
NP_000326.2:p.Arg34His
NP_001092874.1:p.Arg34His
NP_001092875.1:p.Arg34His
NP_001153632.1:p.Arg34His
NP_001153633.1:p.Arg34His
NP_001341630.1:p.Arg34His
NP_932173.1:p.Arg34His
NP_932173.1:p.Arg34His
LRG_289t1:c.101G>A
LRG_289:g.21466G>A
LRG_289p1:p.Arg34His
NC_000003.11:g.38674698C>T
NM_001099404.1:c.101G>A
NM_198056.2:c.101G>A
Q14524:p.Arg34His

Protein change:

R34H

Links:

UniProtKB: Q14524#VAR_074313; dbSNP: rs199473046

NCBI 1000 Genomes Browser:

rs199473046

Molecular consequence:

NM_000335.5:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.101G>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
SCV000089903	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 19841300, 20129283, 22581653
SCV001203078	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28018021, 32880476, 28492532
SCV001813192	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 29, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000089903

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

no classification provided

not provided

germline

literature only

PubMed (3)
[See all records that cite these PMIDs]

SCV001203078

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 16, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001813192

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 29, 2020)

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, literature only

Citations

PubMed

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]

PMID:: 19841300
PMCID:: PMC3025752

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]

PMID:: 20129283
PMCID:: PMC2822446

See all PubMed Citations (6)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089903.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

This variant has been reported in the following publications (PMID:19841300;PMID:20129283).

#	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 Invitae, SCV001203078.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 34 of the SCN5A protein (p.Arg34His). This variant is present in population databases (rs199473046, gnomAD 0.02%). This missense change has been observed in individual(s) with complete heart block or dilated cardiomyopathy (PMID: 28018021, 32880476). ClinVar contains an entry for this variant (Variation ID: 67627). 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 tolerated. 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.

#	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, SCV001813192.1

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

Description

Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#67627; Landrum et al., 2016); 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: 32880476, 28018021, 20129283, 19841300)

#	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: Sep 16, 2024

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