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NM_000335.5(SCN5A):c.4296+1del AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 26, 2021
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:
RCV002329758.2

Allele description [Variation Report for NM_000335.5(SCN5A):c.4296+1del]

NM_000335.5(SCN5A):c.4296+1del

Gene:
SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000335.5(SCN5A):c.4296+1del
HGVS:
  • NC_000003.12:g.38557235del
  • NG_008934.1:g.97443del
  • NM_000335.5:c.4296+1delMANE SELECT
  • NM_001099404.2:c.4299+1del
  • NM_001099405.2:c.4246-652del
  • NM_001160160.2:c.4296+1del
  • NM_001160161.2:c.4137+1del
  • NM_001354701.2:c.4243-652del
  • NM_198056.3:c.4299+1del
  • LRG_289t1:c.4299+1del
  • LRG_289t3:c.4299+1del
  • LRG_289:g.97443del
  • NC_000003.11:g.38598721del
  • NC_000003.11:g.38598726del
  • NM_001099404.1:c.4299+1del
  • NM_198056.2:c.4299+1delG
Links:
dbSNP: rs1450434935
NCBI 1000 Genomes Browser:
rs1450434935
Molecular consequence:
  • NM_001099405.2:c.4246-652del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354701.2:c.4243-652del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000335.5:c.4296+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001099404.2:c.4299+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001160160.2:c.4296+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001160161.2:c.4137+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_198056.3:c.4299+1del - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002629689Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jul 26, 2021) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies.

Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, Mabo P, Bezzina CR, Le Marec H, Wilde AA.

Heart Rhythm. 2009 Mar;6(3):341-8. doi: 10.1016/j.hrthm.2008.11.009. Epub 2008 Nov 11.

PubMed [citation]
PMID:
19251209

Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy.

van Waning JI, Caliskan K, Hoedemaekers YM, van Spaendonck-Zwarts KY, Baas AF, Boekholdt SM, van Melle JP, Teske AJ, Asselbergs FW, Backx APCM, du Marchie Sarvaas GJ, Dalinghaus M, Breur JMPJ, Linschoten MPM, Verlooij LA, Kardys I, Dooijes D, Lekanne Deprez RH, IJpma AS, van den Berg MP, Hofstra RMW, van Slegtenhorst MA, et al.

J Am Coll Cardiol. 2018 Feb 20;71(7):711-722. doi: 10.1016/j.jacc.2017.12.019.

PubMed [citation]
PMID:
29447731
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002629689.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The c.4299+1delG intronic variant, located in intron 23 of the SCN5A gene, results from a deletion of one nucleotide within intron 23 of the SCN5A gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant (also referred to as c.4299delG) has been detected in individuals from Brugada syndrome or cardiac conduction disease cohorts; however, details were limited and reports may overlap (Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8; Berthome P et al. Heart Rhythm, 2019 02;16:260-267). This variant also co-occurred with another variant in a cardiac-related gene in a noncompaction cardiomyopathy cohort (van Waning JI et al. J Am Coll Cardiol, 2018 02;71:711-722). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024