NM_000335.5(SCN5A):c.820G>A (p.Gly274Ser) AND Brugada syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 15, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000199539.6

Allele description [Variation Report for NM_000335.5(SCN5A):c.820G>A (p.Gly274Ser)]

NM_000335.5(SCN5A):c.820G>A (p.Gly274Ser)

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.820G>A (p.Gly274Ser)

Other names:

p.G274S:GGC>AGC

HGVS:

NC_000003.12:g.38609848C>T
NG_008934.1:g.44825G>A
NM_000335.5:c.820G>AMANE SELECT
NM_001099404.2:c.820G>A
NM_001099405.2:c.820G>A
NM_001160160.2:c.820G>A
NM_001160161.2:c.820G>A
NM_001354701.2:c.820G>A
NM_198056.3:c.820G>A
NP_000326.2:p.Gly274Ser
NP_001092874.1:p.Gly274Ser
NP_001092875.1:p.Gly274Ser
NP_001153632.1:p.Gly274Ser
NP_001153633.1:p.Gly274Ser
NP_001341630.1:p.Gly274Ser
NP_932173.1:p.Gly274Ser
NP_932173.1:p.Gly274Ser
LRG_289t1:c.820G>A
LRG_289:g.44825G>A
LRG_289p1:p.Gly274Ser
NC_000003.11:g.38651339C>T
NM_198056.2:c.820G>A

Protein change:

G274S

Links:

dbSNP: rs794728852

NCBI 1000 Genomes Browser:

rs794728852

Molecular consequence:

NM_000335.5:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.820G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000255235	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30193851, 28492532
SCV004697493	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255235

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 1, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004697493

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
Caucasian	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000255235.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 274 of the SCN5A protein (p.Gly274Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 30193851). ClinVar contains an entry for this variant (Variation ID: 201445). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations, SCV004697493.1

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

Description

Variant was found in asymptomatic male patient (37 y.o., Caucasian) with spontaneous Brugada-pattern found on routine ECG-screening. Family history was unremarkable. This substitution affects transmembrane-pore region of Nav1.5 channel. Variant is absent in gnomAD Exomes, and registered in gnomAD Genomes (found in 1 female carrier) with MAF 0.00000657. ClinVar contains an entry for this allele (Variation ID: 201445). All pathogenicity scores support damaging effect on protein. Variant meets criteria PM1_Strong, PM2, PP3 ACMG(2015) and Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls(2021) criteria and was classified as Likely Pathogenic (Class IV of pathogenicity).

#	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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