NM_000335.5(SCN5A):c.4892G>A (p.Arg1631His) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 18, 2023
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:: RCV000519341.9

Allele description [Variation Report for NM_000335.5(SCN5A):c.4892G>A (p.Arg1631His)]

NM_000335.5(SCN5A):c.4892G>A (p.Arg1631His)

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.4892G>A (p.Arg1631His)

HGVS:

NC_000003.12:g.38551477C>T
NG_008934.1:g.103196G>A
NM_000335.5:c.4892G>AMANE SELECT
NM_001099404.2:c.4895G>A
NM_001099405.2:c.4841G>A
NM_001160160.2:c.4796G>A
NM_001160161.2:c.4733G>A
NM_001354701.2:c.4838G>A
NM_198056.3:c.4895G>A
NP_000326.2:p.Arg1631His
NP_001092874.1:p.Arg1632His
NP_001092875.1:p.Arg1614His
NP_001153632.1:p.Arg1599His
NP_001153633.1:p.Arg1578His
NP_001341630.1:p.Arg1613His
NP_932173.1:p.Arg1632His
NP_932173.1:p.Arg1632His
LRG_289t1:c.4895G>A
LRG_289t3:c.4895G>A
LRG_289:g.103196G>A
LRG_289p1:p.Arg1632His
NC_000003.11:g.38592968C>T
NM_001099404.1:c.4895G>A
NM_198056.2:c.4895G>A
NM_198056.3:c.4895G>A

Protein change:

R1578H

Links:

dbSNP: rs199473286

NCBI 1000 Genomes Browser:

rs199473286

Molecular consequence:

NM_000335.5:c.4892G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.4895G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.4841G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.4796G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.4733G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.4838G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.4895G>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
SCV000616867	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 21, 2022)	germline	clinical testing	Citation Link,
SCV000637165	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 18, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 14523039, 24948852, 28781330, 34539730, 35027292, 35124229, 20384651, 20539757, 32533946, 26031372, 27082542, 31191357, 28492532
SCV003812639	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 30, 2021)	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

SCV000616867

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 21, 2022)

germline

clinical testing

Citation Link,

SCV000637165

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 18, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV003812639

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 30, 2021)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).

Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George AL Jr.

J Clin Invest. 2003 Oct;112(7):1019-28.

PubMed [citation]

PMID:: 14523039
PMCID:: PMC198523

Reduced Penetrance and Variable Expression of SCN5A Mutations and the Importance of Co-inherited Genetic Variants: Case Report and Review of the Literature.

Robyns T, Nuyens D, Van Casteren L, Corveleyn A, De Ravel T, Heidbuchel H, Willems R.

Indian Pacing Electrophysiol J. 2014 May;14(3):133-49.

PubMed [citation]

PMID:: 24948852
PMCID:: PMC4032780

See all PubMed Citations (14)

Details of each submission

From GeneDx, SCV000616867.6

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

Description

Observed in the heterozygous state in patients with Brugada syndrome and in the compound heterozygous state with a second SCN5A variant in patients with sick sinus syndrome, and segregated with SCN5A-related phenotypes in relatives from unrelated families in the published literature (Benson et al., 2003; van Malderen et al., 2017; Robyns et al., 2014; Robyns et al., 2018; Liu et al., 2021); Published functional studies demonstrate a damaging effect on channel kinetics (Benson et al., 2003; Gui et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27381756, 20384651, 25863800, 20539757, 28018021, 17368591, 31521807, 32850980, 31447099, 33131149, 29709101, 29728395, 24948852, 28781330, 26582918, 14523039, 34539730)

#	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, SCV000637165.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1632 of the SCN5A protein (p.Arg1632His). This variant is present in population databases (rs199473286, gnomAD 0.003%). This missense change has been observed in individuals with Brugada syndrome or sick sinus syndrome (PMID: 14523039, 24948852, 28781330, 34539730, 35027292, 35124229). ClinVar contains an entry for this variant (Variation ID: 67939). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 20384651, 20539757, 32533946). This variant disrupts the p.Arg1632 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26031372, 27082542, 31191357). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV003812639.2

#	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: Nov 10, 2024

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