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NM_000335.5(SCN5A):c.1457C>G (p.Thr486Ser) AND Brugada syndrome 1

Germline classification:
Uncertain significance (1 submission)
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:
RCV004698530.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.1457C>G (p.Thr486Ser)]

NM_000335.5(SCN5A):c.1457C>G (p.Thr486Ser)

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.1457C>G (p.Thr486Ser)
HGVS:
  • NC_000003.12:g.38604790G>C
  • NG_008934.1:g.49883C>G
  • NM_000335.5:c.1457C>GMANE SELECT
  • NM_001099404.2:c.1457C>G
  • NM_001099405.2:c.1457C>G
  • NM_001160160.2:c.1457C>G
  • NM_001160161.2:c.1457C>G
  • NM_001354701.2:c.1457C>G
  • NM_198056.3:c.1457C>G
  • NP_000326.2:p.Thr486Ser
  • NP_001092874.1:p.Thr486Ser
  • NP_001092875.1:p.Thr486Ser
  • NP_001153632.1:p.Thr486Ser
  • NP_001153633.1:p.Thr486Ser
  • NP_001341630.1:p.Thr486Ser
  • NP_932173.1:p.Thr486Ser
  • NP_932173.1:p.Thr486Ser
  • LRG_289t1:c.1457C>G
  • LRG_289:g.49883C>G
  • LRG_289p1:p.Thr486Ser
  • NC_000003.11:g.38646281G>C
  • NM_198056.2:c.1457C>G
Protein change:
T486S
Links:
dbSNP: rs1274970281
NCBI 1000 Genomes Browser:
rs1274970281
Molecular consequence:
  • NM_000335.5:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099404.2:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001099405.2:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160160.2:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160161.2:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354701.2:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198056.3:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005200470Roden Lab, Vanderbilt University Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significancegermline, not applicableresearch, in vitro

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch
not providednot applicablenot applicablenot providednot providednot providednot providednot providedin vitro

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. Update in: Nat Commun. 2024 Sep 27;15(1):8320. doi: 10.1038/s41467-024-52474-4..

PubMed [citation]
PMID:
37732247
PMCID:
PMC10508793

Details of each submission

From Roden Lab, Vanderbilt University Medical Center, SCV005200470.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)
2not providednot providednot providednot providedin 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, 3-38604790-G-C was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.2; 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2not applicablenot applicablenot providednot providedassert pathogenicitynot providednot providednot providednot provided

Last Updated: May 25, 2025