NM_000335.5(SCN5A):c.250G>A (p.Asp84Asn) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 16, 2024
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:: RCV003556149.3

Allele description [Variation Report for NM_000335.5(SCN5A):c.250G>A (p.Asp84Asn)]

NM_000335.5(SCN5A):c.250G>A (p.Asp84Asn)

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.250G>A (p.Asp84Asn)

HGVS:

NC_000003.12:g.38633058C>T
NG_008934.1:g.21615G>A
NM_000335.5:c.250G>AMANE SELECT
NM_001099404.2:c.250G>A
NM_001099405.2:c.250G>A
NM_001160160.2:c.250G>A
NM_001160161.2:c.250G>A
NM_001354701.2:c.250G>A
NM_198056.3:c.250G>A
NP_000326.2:p.Asp84Asn
NP_001092874.1:p.Asp84Asn
NP_001092875.1:p.Asp84Asn
NP_001153632.1:p.Asp84Asn
NP_001153633.1:p.Asp84Asn
NP_001341630.1:p.Asp84Asn
NP_932173.1:p.Asp84Asn
NP_932173.1:p.Asp84Asn
LRG_289t1:c.250G>A
LRG_289:g.21615G>A
LRG_289p1:p.Asp84Asn
NC_000003.11:g.38674549C>T
NM_198056.2:c.250G>A
Q14524:p.Asp84Asn

Protein change:

D84N

Links:

UniProtKB: Q14524#VAR_074315; dbSNP: rs199473051

NCBI 1000 Genomes Browser:

rs199473051

Molecular consequence:

NM_000335.5:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.250G>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
SCV004292676	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 8, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20129283, 30193851, 32533946, 28492532
SCV005201556	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 16, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004292676

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 8, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005201556

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 16, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, et al.

Heart Rhythm. 2010 Jan;7(1):33-46. doi: 10.1016/j.hrthm.2009.09.069. Epub 2009 Oct 8.

PubMed [citation]

PMID:: 20129283
PMCID:: PMC2822446

Clinical presentation and follow-up of women affected by Brugada syndrome.

Berthome P, Tixier R, Briand J, Geoffroy O, Babuty D, Mansourati J, Jesel L, Dupuis JM, Bru P, Kyndt F, Guyomarch B, Thollet A, Behar N, Mabo P, Sacher F, Probst V, Gourraud JB.

Heart Rhythm. 2019 Feb;16(2):260-267. doi: 10.1016/j.hrthm.2018.08.032. Epub 2018 Sep 5.

PubMed [citation]

PMID:: 30193851

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004292676.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 84 of the SCN5A protein (p.Asp84Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 20129283, 30193851). ClinVar contains an entry for this variant (Variation ID: 67736). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 GeneDx, SCV005201556.1

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

Description

Identified in patients with Brugada syndrome in published literature (PMID: 20129283, 25904541, 30193851, 32533946); Not observed at significant frequency in large population cohorts (gnomAD); A published functional study suggests a reduction in channel peak current density (PMID: 32533946); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25904541, 30662450, 30203441, 30193851, 20129283, 32533946)

#	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: Sep 29, 2024

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