NM_000335.5(SCN5A):c.3142_3153delinsTCTGACTGTGT (p.Pro1048fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 8, 2021
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:: RCV000183158.13

Allele description [Variation Report for NM_000335.5(SCN5A):c.3142_3153delinsTCTGACTGTGT (p.Pro1048fs)]

NM_000335.5(SCN5A):c.3142_3153delinsTCTGACTGTGT (p.Pro1048fs)

Genes:

LOC110121269:VISTA enhancer hs2177 [Gene]
SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.3142_3153delinsTCTGACTGTGT (p.Pro1048fs)

HGVS:

NC_000003.12:g.38581006_38581017delinsACACAGTCAGA
NG_008934.1:g.73656_73667delinsTCTGACTGTGT
NG_053884.1:g.2745_2756delinsACACAGTCAGA
NM_000335.5:c.3142_3153delinsTCTGACTGTGTMANE SELECT
NM_001099404.2:c.3142_3153delinsTCTGACTGTGT
NM_001099405.2:c.3142_3153delinsTCTGACTGTGT
NM_001160160.2:c.3142_3153delinsTCTGACTGTGT
NM_001160161.2:c.3142_3153delinsTCTGACTGTGT
NM_001354701.2:c.3142_3153delinsTCTGACTGTGT
NM_198056.3:c.3142_3153delinsTCTGACTGTGT
NP_000326.2:p.Pro1048fs
NP_001092874.1:p.Pro1048fs
NP_001092875.1:p.Pro1048fs
NP_001153632.1:p.Pro1048fs
NP_001153633.1:p.Pro1048fs
NP_001341630.1:p.Pro1048fs
NP_932173.1:p.Pro1048fs
LRG_289:g.73656_73667delinsTCTGACTGTGT
NC_000003.11:g.38622497_38622508delinsACACAGTCAGA
NM_001099404.1:c.3142_3153delinsTCTGACTGTGT
NM_198056.2:c.3142_3153del12insTCTGACTGTGT
NM_198056.2:c.3142_3153delCCCATCGCTGTGinsTCTGACTGTGT
p.P1048SfsX97

Protein change:

P1048fs

Links:

dbSNP: rs794728917

NCBI 1000 Genomes Browser:

rs794728917

Molecular consequence:

NM_000335.5:c.3142_3153delinsTCTGACTGTGT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001099404.2:c.3142_3153delinsTCTGACTGTGT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001099405.2:c.3142_3153delinsTCTGACTGTGT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001160160.2:c.3142_3153delinsTCTGACTGTGT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001160161.2:c.3142_3153delinsTCTGACTGTGT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354701.2:c.3142_3153delinsTCTGACTGTGT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_198056.3:c.3142_3153delinsTCTGACTGTGT - 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
SCV000235574	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 3, 2019)	germline	clinical testing	Citation Link,
SCV004673466	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 8, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25171853, 20129283, 22789973, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235574

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 3, 2019)

germline

clinical testing

Citation Link,

SCV004673466

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 8, 2021)

germline

clinical testing

PubMed (4)
[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

Compound heterozygous mutations in the SCN5A-encoded Nav1.5 cardiac sodium channel resulting in atrial standstill and His-Purkinje system disease.

Baskar S, Ackerman MJ, Clements D, Mayuga KA, Aziz PF.

J Pediatr. 2014 Nov;165(5):1050-2. doi: 10.1016/j.jpeds.2014.07.036. Epub 2014 Aug 27.

PubMed [citation]

PMID:: 25171853

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 (4)

Details of each submission

From GeneDx, SCV000235574.13

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

Description

Frameshift 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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25171853)

#	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, SCV004673466.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This premature translational stop signal has been observed in individual(s) with clinical features of SCN5A-related disease (PMID: 25171853). The frequency data for this variant in the population databases is not available, as this variant may be reported as separate entries in the ExAC database. This sequence change creates a premature translational stop signal (p.Pro1048Serfs*97) 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).

#	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: Nov 24, 2024

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