NM_000335.5(SCN5A):c.1127G>A (p.Arg376His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 24, 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:: RCV000182960.18

Allele description [Variation Report for NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)]

NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)

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.1127G>A (p.Arg376His)

Other names:

p.R376H:CGC>CAC

HGVS:

NC_000003.12:g.38606682C>T
NG_008934.1:g.47991G>A
NM_000335.5:c.1127G>AMANE SELECT
NM_001099404.2:c.1127G>A
NM_001099405.2:c.1127G>A
NM_001160160.2:c.1127G>A
NM_001160161.2:c.1127G>A
NM_001354701.2:c.1127G>A
NM_198056.3:c.1127G>A
NP_000326.2:p.Arg376His
NP_001092874.1:p.Arg376His
NP_001092875.1:p.Arg376His
NP_001153632.1:p.Arg376His
NP_001153633.1:p.Arg376His
NP_001341630.1:p.Arg376His
NP_932173.1:p.Arg376His
NP_932173.1:p.Arg376His
LRG_289t1:c.1127G>A
LRG_289:g.47991G>A
LRG_289p1:p.Arg376His
NC_000003.11:g.38648173C>T
NM_198056.2:c.1127G>A
NM_198056.3:c.1127G>A
Q14524:p.Arg376His

Protein change:

R376H

Links:

UniProtKB: Q14524#VAR_055169; dbSNP: rs199473101

NCBI 1000 Genomes Browser:

rs199473101

Molecular consequence:

NM_000335.5:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235357	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 24, 2024)	germline	clinical testing	Citation Link,
SCV000760186	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 16344400, 18378609, 20129283, 23671135, 25194972, 27930701, 28341781, 15851228, 21840964, 24295898, 28492532
SCV002020029	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235357

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Apr 24, 2024)

germline

clinical testing

Citation Link,

SCV000760186

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 17, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002020029

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 26, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome.

Frustaci A, Priori SG, Pieroni M, Chimenti C, Napolitano C, Rivolta I, Sanna T, Bellocci F, Russo MA.

Circulation. 2005 Dec 13;112(24):3680-7.

PubMed [citation]

PMID:: 16344400

Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.

Darbar D, Kannankeril PJ, Donahue BS, Kucera G, Stubblefield T, Haines JL, George AL Jr, Roden DM.

Circulation. 2008 Apr 15;117(15):1927-35. doi: 10.1161/CIRCULATIONAHA.107.757955. Epub 2008 Mar 31.

PubMed [citation]

PMID:: 18378609
PMCID:: PMC2365761

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000235357.17

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

Description

Published functional studies demonstrate this variant results in a significant reduction of the inward sodium current (PMID: 15851228, 21840964, 24295898); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17512504, 20129283, 28341781, 34461752, 15851228, 23414114, 25194972, 18378609, 16344400, 23671135, 27930701, 21840964, 31737537, 30193851, 30662450, 29709101, 33164571, 33131149, 30203441, 34495297, 24295898)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000760186.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 376 of the SCN5A protein (p.Arg376His). This variant is present in population databases (rs199473101, gnomAD 0.004%). This missense change has been observed in individuals with Brugada syndrome (PMID: 15851228, 16344400, 18378609, 20129283, 23671135, 25194972, 27930701, 28341781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67639). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15851228, 21840964, 24295898). For these reasons, this variant has been classified as Pathogenic.

#	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 Revvity Omics, Revvity, SCV002020029.3

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

#	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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine