NM_000335.5(SCN5A):c.3943C>T (p.Arg1315Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 8, 2023
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:: RCV000681957.4

Allele description [Variation Report for NM_000335.5(SCN5A):c.3943C>T (p.Arg1315Ter)]

NM_000335.5(SCN5A):c.3943C>T (p.Arg1315Ter)

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.3943C>T (p.Arg1315Ter)

HGVS:

NC_000003.12:g.38562432G>A
NG_008934.1:g.92241C>T
NM_000335.5:c.3943C>TMANE SELECT
NM_001099404.2:c.3946C>T
NM_001099405.2:c.3946C>T
NM_001160160.2:c.3943C>T
NM_001160161.2:c.3784C>T
NM_001354701.2:c.3943C>T
NM_198056.3:c.3946C>T
NP_000326.2:p.Arg1315Ter
NP_001092874.1:p.Arg1316Ter
NP_001092875.1:p.Arg1316Ter
NP_001153632.1:p.Arg1315Ter
NP_001153633.1:p.Arg1262Ter
NP_001341630.1:p.Arg1315Ter
NP_932173.1:p.Arg1316Ter
NP_932173.1:p.Arg1316Ter
LRG_289t1:c.3946C>T
LRG_289:g.92241C>T
LRG_289p1:p.Arg1316Ter
NC_000003.11:g.38603923G>A
NM_198056.2:c.3946C>T

Protein change:

R1262*

Links:

dbSNP: rs1553695764

NCBI 1000 Genomes Browser:

rs1553695764

Molecular consequence:

NM_000335.5:c.3943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001099404.2:c.3946C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001099405.2:c.3946C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001160160.2:c.3943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001160161.2:c.3784C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354701.2:c.3943C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198056.3:c.3946C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000809452	Gharavi Laboratory, Columbia University	no assertion criteria provided (ACMG Guidelines, 2015)	Likely pathogenic (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001399379	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20129283, 22789973, 19561025, 30828344, 28492532
SCV001756144	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 26, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000809452

Gharavi Laboratory, Columbia University

no assertion criteria provided

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 16, 2018)

germline

research

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

SCV001399379

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001756144

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 26, 2020)

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, research
not provided	germline	unknown	not provided	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

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

See all PubMed Citations (6)

Details of each submission

From Gharavi Laboratory, Columbia University, SCV000809452.1

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

#	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

From Invitae, SCV001399379.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg1316*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Brugada syndrome (PMID: 19561025, 30828344). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 496571). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	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, SCV001756144.1

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

Description

Reported in ClinVar as likely pathogenic and pathogenic (ClinVar Variant ID# 496571; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31447099, 30828344, 19561025)

#	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: Jul 29, 2024

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