NM_000335.5(SCN5A):c.5527_5530dup (p.Gly1844fs) AND Brugada syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 20, 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:: RCV004003324.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.5527_5530dup (p.Gly1844fs)]

NM_000335.5(SCN5A):c.5527_5530dup (p.Gly1844fs)

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.5527_5530dup (p.Gly1844fs)

HGVS:

NC_000003.12:g.38550842_38550845dup
NG_008934.1:g.103831_103834dup
NM_000335.5:c.5527_5530dupMANE SELECT
NM_001099404.2:c.5530_5533dup
NM_001099405.2:c.5476_5479dup
NM_001160160.2:c.5431_5434dup
NM_001160161.2:c.5368_5371dup
NM_001354701.2:c.5473_5476dup
NM_198056.2:c.5530_5533dup
NM_198056.3:c.5530_5533dup
NP_000326.2:p.Gly1844fs
NP_001092874.1:p.Gly1845fs
NP_001092875.1:p.Gly1827fs
NP_001153632.1:p.Gly1812fs
NP_001153633.1:p.Gly1791fs
NP_001341630.1:p.Gly1826fs
NP_932173.1:p.Gly1845fs
LRG_289t1:c.5530_5533dup
LRG_289:g.103831_103834dup
NC_000003.11:g.38592333_38592336dup
NM_198056.2:c.5533_5534insAGTG

Protein change:

G1791fs

Links:

dbSNP: rs1064794424

NCBI 1000 Genomes Browser:

rs1064794424

Molecular consequence:

NM_000335.5:c.5527_5530dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001099404.2:c.5530_5533dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001099405.2:c.5476_5479dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001160160.2:c.5431_5434dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001160161.2:c.5368_5371dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354701.2:c.5473_5476dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_198056.3:c.5530_5533dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Brugada syndrome
Synonyms:: Sudden unexpected nocturnal death syndrome; Sudden unexplained nocturnal death syndrome; Sudden Unexplained Death Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015263; MedGen: C1142166; OMIM: PS601144

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004840237	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10684611, 11884381, 24582607, 32893267, 34575961, 34643236, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004840237

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (7)
[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

Novel interaction of the voltage-dependent sodium channel (VDSC) with calmodulin: does VDSC acquire calmodulin-mediated Ca2+-sensitivity?

Mori M, Konno T, Ozawa T, Murata M, Imoto K, Nagayama K.

Biochemistry. 2000 Feb 15;39(6):1316-23.

PubMed [citation]

PMID:: 10684611

Isoform-specific modulation of voltage-gated Na(+) channels by calmodulin.

Deschênes I, Neyroud N, DiSilvestre D, Marbán E, Yue DT, Tomaselli GF.

Circ Res. 2002 Mar 8;90(4):E49-57.

PubMed [citation]

PMID:: 11884381

See all PubMed Citations (7)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004840237.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

This variant causes a duplication of four nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the sequence of C-terminal domain (a.a. 1773-2016) that includes a functionally important calmodulin-binding motif (a.a.1898-1924) (PMID: 10684611, 11884381, 34575961, 34643236) and is enriched with rare non-truncating variants overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different frameshift variant occurring in the nearby region, p.Arg1860Glyfs*12 (c.5578del), has been shown to segregate with sick sinus syndrome in a family (PMID: 24582607) and has been shown to disrupt protein stability in a functional study (PMID: 24582607). 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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