NM_000335.5(SCN5A):c.5620_5622dup (p.Met1874dup) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 28, 2023
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:: RCV004002746.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.5620_5622dup (p.Met1874dup)]

NM_000335.5(SCN5A):c.5620_5622dup (p.Met1874dup)

Gene:

SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.5620_5622dup (p.Met1874dup)

HGVS:

NC_000003.12:g.38550748_38550750dup
NG_008934.1:g.103924_103926dup
NM_000335.5:c.5620_5622dupMANE SELECT
NM_001099404.2:c.5623_5625dup
NM_001099405.2:c.5569_5571dup
NM_001160160.2:c.5524_5526dup
NM_001160161.2:c.5461_5463dup
NM_001354701.2:c.5566_5568dup
NM_198056.3:c.5623_5625dup
NP_000326.2:p.Met1874dup
NP_001092874.1:p.Met1875dup
NP_001092875.1:p.Met1857dup
NP_001153632.1:p.Met1842dup
NP_001153633.1:p.Met1821dup
NP_001341630.1:p.Met1856dup
NP_932173.1:p.Met1875dup
LRG_289t2:c.5620_5622dup
LRG_289:g.103924_103926dup
NC_000003.11:g.38592237_38592238insCAT
NC_000003.11:g.38592239_38592241dup
NM_000335.4:c.5620_5622dupATG
NM_198056.2:c.5623_5625dupATG

Links:

dbSNP: rs1474459822

NCBI 1000 Genomes Browser:

rs1474459822

Molecular consequence:

NM_000335.5:c.5620_5622dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001099404.2:c.5623_5625dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001099405.2:c.5569_5571dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001160160.2:c.5524_5526dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001160161.2:c.5461_5463dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001354701.2:c.5566_5568dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_198056.3:c.5623_5625dup - inframe_insertion - [Sequence Ontology: SO:0001821]

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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membrane steroid-binding protein 2 [Cucumis sativus]
membrane steroid-binding protein 2 [Cucumis sativus]
gi|449437656|ref|XP_004136607.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004828092	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19272188, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004828092

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 28, 2023)

germline

clinical testing

PubMed (3)
[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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations.

Hsueh CH, Chen WP, Lin JL, Tsai CT, Liu YB, Juang JM, Tsao HM, Su MJ, Lai LP.

J Biomed Sci. 2009 Feb 20;16:23. doi: 10.1186/1423-0127-16-23.

PubMed [citation]

PMID:: 19272188
PMCID:: PMC2653527

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, Amin AS, Nannenberg EA, Ware JS, Whiffin N, Mazzarotto F, Škorić-Milosavljević D, Krijger C, Arbelo E, Babuty D, Barajas-Martinez H, Beckmann BM, Bézieau S, Bos JM, Breckpot J, Campuzano O, Castelletti S, et al.

Genet Med. 2021 Jan;23(1):47-58. doi: 10.1038/s41436-020-00946-5. Epub 2020 Sep 7.

PubMed [citation]

PMID:: 32893267
PMCID:: PMC7790744

See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004828092.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This variant causes a duplication of methionine at codon 1875 of the SCN5A protein. This variant is also known as p.Met1874dup based on a different transcript NM_000335.5. This variant is found within the highly conserved C-terminal region (a.a. 1773-2016). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant traffics to the cell surface similarly to wildtype channels, but has altered electrophysiological properties (PMID: 19272188). This variant has been reported in an individual affected with Brugada syndrome (PMID: 19272188). This variant has been identified in 2/280672 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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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