NM_000335.5(SCN5A):c.611C>T (p.Ala204Val) AND Brugada syndrome 1

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 16, 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:: RCV003989314.4

Allele description [Variation Report for NM_000335.5(SCN5A):c.611C>T (p.Ala204Val)]

NM_000335.5(SCN5A):c.611C>T (p.Ala204Val)

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.611C>T (p.Ala204Val)

HGVS:

NC_000003.12:g.38620843G>A
NG_008934.1:g.33830C>T
NM_000335.5:c.611C>TMANE SELECT
NM_001099404.2:c.611C>T
NM_001099405.2:c.611C>T
NM_001160160.2:c.611C>T
NM_001160161.2:c.611C>T
NM_001354701.2:c.611C>T
NM_198056.3:c.611C>T
NP_000326.2:p.Ala204Val
NP_001092874.1:p.Ala204Val
NP_001092875.1:p.Ala204Val
NP_001153632.1:p.Ala204Val
NP_001153633.1:p.Ala204Val
NP_001341630.1:p.Ala204Val
NP_932173.1:p.Ala204Val
NP_932173.1:p.Ala204Val
LRG_289t1:c.611C>T
LRG_289:g.33830C>T
LRG_289p1:p.Ala204Val
NC_000003.11:g.38662334G>A
NM_198056.2:c.611C>T
NM_198056.3:c.611C>T
Q14524:p.Ala204Val

Protein change:

A204V

Links:

UniProtKB: Q14524#VAR_074330; dbSNP: rs199473559

NCBI 1000 Genomes Browser:

rs199473559

Molecular consequence:

NM_000335.5:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.611C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

Observations:

Condition(s)

Name:: Brugada syndrome 1 (BRGDA1)
Synonyms:: Right bundle branch block, ST segment elevation, and sudden death syndrome
Identifiers:: MONDO: MONDO:0011001; MedGen: C4551804; Orphanet: 130; OMIM: 601144

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004806692	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005050130	KardioGenetik, Herz- und Diabeteszentrum NRW	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 16, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005200464	Roden Lab, Vanderbilt University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline, not applicable	research, in vitro	PubMed (2) [See all records that cite these PMIDs] 25741868, 37732247

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004806692

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 26, 2024)

germline

clinical testing

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

SCV005050130

KardioGenetik, Herz- und Diabeteszentrum NRW

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 16, 2024)

unknown

clinical testing

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

SCV005200464

Roden Lab, Vanderbilt University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline, not applicable

research, in vitro

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

ParSE-seq: A Calibrated Multiplexed Assay to Facilitate the Clinical Classification of Putative Splice-altering Variants.

O'Neill MJ, Yang T, Laudeman J, Calandranis M, Solus J, Roden DM, Glazer AM.

medRxiv. 2023 Sep 8. doi:pii: 2023.09.04.23295019. 10.1101/2023.09.04.23295019.

PubMed [citation]

PMID:: 37732247
PMCID:: PMC10508793

Details of each submission

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806692.1

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

#	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 KardioGenetik, Herz- und Diabeteszentrum NRW, SCV005050130.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Roden Lab, Vanderbilt University Medical Center, SCV005200464.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	in vitro	PubMed (2)

Description

"Functional evidence assertions with RNA-splicing scores. Benign RNA-splicing scores were not applied to missense variants."

PubMed [ID: 37732247]

Description

We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38620843-G-A was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.0000131 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.0694; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data.

#	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
2	not applicable	not applicable	not provided	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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