NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met) AND Cardiac arrhythmia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 28, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001842371.11

Allele description [Variation Report for NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met)]

NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met)

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.4856C>T (p.Thr1619Met)

HGVS:

NC_000003.12:g.38551513G>A
NG_008934.1:g.103160C>T
NM_000335.5:c.4856C>TMANE SELECT
NM_001099404.2:c.4859C>T
NM_001099405.2:c.4805C>T
NM_001160160.2:c.4760C>T
NM_001160161.2:c.4697C>T
NM_001354701.2:c.4802C>T
NM_198056.3:c.4859C>T
NP_000326.2:p.Thr1619Met
NP_001092874.1:p.Thr1620Met
NP_001092875.1:p.Thr1602Met
NP_001153632.1:p.Thr1587Met
NP_001153633.1:p.Thr1566Met
NP_001341630.1:p.Thr1601Met
NP_932173.1:p.Thr1620Met
NP_932173.1:p.Thr1620Met
LRG_289t1:c.4859C>T
LRG_289t2:c.4856C>T
LRG_289:g.103160C>T
NC_000003.11:g.38593004G>A
NM_000335.4:c.4856C>T
NM_198056.2:c.4859C>T
Q14524:p.Thr1620Met

Protein change:

T1566M; THR1620MET

Links:

UniProtKB: Q14524#VAR_017684; OMIM: 600163.0004; dbSNP: rs199473282

NCBI 1000 Genomes Browser:

rs199473282

Molecular consequence:

NM_000335.5:c.4856C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.4859C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.4805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.4760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.4697C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.4802C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.4859C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001340219	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 28, 2021)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9521325, 10532948, 10618304, 10662748, 11029409, 11123251, 11827685, 15520322, 20129283, 25904541, 30050137, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001340219

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 28, 2021)

germline

clinical testing

PubMed (12)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.

Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O'Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q.

Nature. 1998 Mar 19;392(6673):293-6.

PubMed [citation]

PMID:: 9521325

Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.

Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, Antzelevitch C.

Circ Res. 1999 Oct 29;85(9):803-9.

PubMed [citation]

PMID:: 10532948

See all PubMed Citations (12)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001340219.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This missense variant replaces threonine with methionine at codon 1620 in the transmembrane domain DIV 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). Multiple functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541) and has been shown to segregate with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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

Last Updated: Apr 20, 2024

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