NM_000335.5(SCN5A):c.5689C>T (p.Arg1897Cys) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 1, 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:: RCV001841789.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.5689C>T (p.Arg1897Cys)]

NM_000335.5(SCN5A):c.5689C>T (p.Arg1897Cys)

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.5689C>T (p.Arg1897Cys)

HGVS:

NC_000003.12:g.38550680G>A
NG_008934.1:g.103993C>T
NM_000335.5:c.5689C>TMANE SELECT
NM_001099404.2:c.5692C>T
NM_001099405.2:c.5638C>T
NM_001160160.2:c.5593C>T
NM_001160161.2:c.5530C>T
NM_001354701.2:c.5635C>T
NM_198056.3:c.5692C>T
NP_000326.2:p.Arg1897Cys
NP_001092874.1:p.Arg1898Cys
NP_001092875.1:p.Arg1880Cys
NP_001153632.1:p.Arg1865Cys
NP_001153633.1:p.Arg1844Cys
NP_001341630.1:p.Arg1879Cys
NP_932173.1:p.Arg1898Cys
NP_932173.1:p.Arg1898Cys
LRG_289t1:c.5692C>T
LRG_289:g.103993C>T
LRG_289p1:p.Arg1898Cys
NC_000003.11:g.38592171G>A
NM_198056.2:c.5692C>T

Protein change:

R1844C

Links:

dbSNP: rs373118001

NCBI 1000 Genomes Browser:

rs373118001

Molecular consequence:

NM_000335.5:c.5689C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5692C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5638C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5593C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5530C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5635C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5692C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001343957	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26173111, 29306897, 29447731, 32533946, 25741868
SCV004823248	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26173111, 29306897, 29447731, 32533946, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001343957

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 27, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004823248

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	13	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Comprehensive Genetic Characterization of a Spanish Brugada Syndrome Cohort.

Selga E, Campuzano O, Pinsach-Abuin ML, Pérez-Serra A, Mademont-Soler I, Riuró H, Picó F, Coll M, Iglesias A, Pagans S, Sarquella-Brugada G, Berne P, Benito B, Brugada J, Porres JM, López Zea M, Castro-Urda V, Fernández-Lozano I, Brugada R.

PLoS One. 2015;10(7):e0132888. doi: 10.1371/journal.pone.0132888.

PubMed [citation]

PMID:: 26173111
PMCID:: PMC4501715

Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population.

Huang L, Wu KH, Zhang L, Wang Q, Tang S, Wu Q, Jiang PH, Lin JJ, Guo J, Wang L, Loh SH, Cheng J.

J Am Heart Assoc. 2018 Jan 6;7(1). doi:pii: e006320. 10.1161/JAHA.117.006320.

PubMed [citation]

PMID:: 29306897
PMCID:: PMC5778954

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001343957.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with cysteine at codon 1898 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant had 28% of the peak current density compared to wild type (PMID: 32533946). This variant has been reported in two individuals affected with Brugada syndrome (PMID: 26173111, 29306897). One of these individuals carried a pathogenic truncation variant in the same gene that could explain the observed phenotype. This variant has also been reported in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). This variant has been identified in 10/280692 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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 All of Us Research Program, National Institutes of Health, SCV004823248.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with cysteine at codon 1898 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the variant protein exhibit 28% of the peak current density compared to wild type protein (PMID: 32533946). This variant has been reported in two individuals affected with Brugada syndrome (PMID: 26173111, 29306897). One of these individuals carried a pathogenic truncation variant in the same gene that could explain the observed phenotype. This variant has also been reported in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). This variant has been identified in 10/280692 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		13	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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