NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 3, 2022
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:: RCV001699194.5

Allele description [Variation Report for NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys)]

NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys)

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.481G>A (p.Glu161Lys)

HGVS:

NC_000003.12:g.38622401C>T
NG_008934.1:g.32272G>A
NM_000335.5:c.481G>AMANE SELECT
NM_001099404.2:c.481G>A
NM_001099405.2:c.481G>A
NM_001160160.2:c.481G>A
NM_001160161.2:c.481G>A
NM_001354701.2:c.481G>A
NM_198056.3:c.481G>A
NP_000326.2:p.Glu161Lys
NP_001092874.1:p.Glu161Lys
NP_001092875.1:p.Glu161Lys
NP_001153632.1:p.Glu161Lys
NP_001153633.1:p.Glu161Lys
NP_001341630.1:p.Glu161Lys
NP_932173.1:p.Glu161Lys
NP_932173.1:p.Glu161Lys
LRG_289t1:c.481G>A
LRG_289:g.32272G>A
LRG_289p1:p.Glu161Lys
NC_000003.11:g.38663892C>T
NM_198056.2:c.481G>A
Q14524:p.Glu161Lys

Protein change:

E161K

Links:

UniProtKB: Q14524#VAR_026344; dbSNP: rs199473062

NCBI 1000 Genomes Browser:

rs199473062

Molecular consequence:

NM_000335.5:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.481G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.481G>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
SCV000545051	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20539757, 15910881, 20031634, 21273195, 28492532
SCV001918589	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001930723	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001954169	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

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

Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome.

Gui J, Wang T, Jones RP, Trump D, Zimmer T, Lei M.

PLoS One. 2010 Jun 7;5(6):e10985. doi: 10.1371/journal.pone.0010985. Erratum in: PLoS One. 2010;5(6). doi: 10.1371/annotation/1230d58a-8d86-4a5c-8918-0a2c513839be. PLoS One. 2010;5(7) doi: 10.1371/annotation/b8de07e2-fd0a-4ae3-bfe6-0eb565da0f75.

PubMed [citation]

PMID:: 20539757
PMCID:: PMC2881866

A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families.

Smits JP, Koopmann TT, Wilders R, Veldkamp MW, Opthof T, Bhuiyan ZA, Mannens MM, Balser JR, Tan HL, Bezzina CR, Wilde AA.

J Mol Cell Cardiol. 2005 Jun;38(6):969-81. Epub 2005 Apr 1.

PubMed [citation]

PMID:: 15910881

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000545051.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15910881, 20539757). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 67927). This missense change has been observed in individuals with Brugada syndrome (PMID: 15910881, 20031634, 21273195). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 161 of the SCN5A protein (p.Glu161Lys).

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001918589.1

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

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001930723.1

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

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954169.1

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

#	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: Aug 11, 2024

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