NM_000335.5(SCN5A):c.4191del (p.Val1399fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 5, 2020
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:: RCV000479877.3

Allele description [Variation Report for NM_000335.5(SCN5A):c.4191del (p.Val1399fs)]

NM_000335.5(SCN5A):c.4191del (p.Val1399fs)

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.4191del (p.Val1399fs)

HGVS:

NC_000003.12:g.38560198del
NG_008934.1:g.94475del
NM_000335.5:c.4191delMANE SELECT
NM_001099404.2:c.4194del
NM_001099405.2:c.4194del
NM_001160160.2:c.4191del
NM_001160161.2:c.4032del
NM_001354701.2:c.4191del
NM_198056.3:c.4194del
NP_000326.2:p.Val1399fs
NP_001092874.1:p.Val1400fs
NP_001092875.1:p.Val1400fs
NP_001153632.1:p.Val1399fs
NP_001153633.1:p.Val1346fs
NP_001341630.1:p.Val1399fs
NP_932173.1:p.Val1400fs
LRG_289:g.94475del
NC_000003.11:g.38601689del
NM_198056.2:c.4194delG

Protein change:

V1346fs

Links:

dbSNP: rs1064796233

NCBI 1000 Genomes Browser:

rs1064796233

Molecular consequence:

NM_000335.5:c.4191del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001099404.2:c.4194del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001099405.2:c.4194del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001160160.2:c.4191del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001160161.2:c.4032del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354701.2:c.4191del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_198056.3:c.4194del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000572755	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Jan 18, 2017)	germline	clinical testing	Citation Link,
SCV001578819	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 5, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20129283, 22789973, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000572755

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Jan 18, 2017)

germline

clinical testing

Citation Link,

SCV001578819

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 5, 2020)

germline

clinical testing

PubMed (3)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Brugada syndrome 2012.

Berne P, Brugada J.

Circ J. 2012;76(7):1563-71. Epub 2012 Jun 13. Review.

PubMed [citation]

PMID:: 22789973

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000572755.3

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

Description

Although the c.4194delG likely pathogenic variant in the SCN5A gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon valine (Val) 1400, changing it to a serine (Ser), and creating a premature stop codon at position 63 of the new reading frame, denoted p.Val1400SerfsX63. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the SCN5A gene have been reported in the Human Gene Mutation Database in association with SCN5A-related disorders (Stenson et al., 2014). Furthermore, the c.4194delG variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001578819.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant has not been reported in the literature in individuals with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 423108). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val1400Serfs*63) in the SCN5A gene. It is expected to result in an absent or disrupted protein product.

#	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

Last Updated: Oct 13, 2024

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