NM_000335.5(SCN5A):c.1003T>C (p.Cys335Arg) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 6, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001751747.4

Allele description [Variation Report for NM_000335.5(SCN5A):c.1003T>C (p.Cys335Arg)]

NM_000335.5(SCN5A):c.1003T>C (p.Cys335Arg)

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.1003T>C (p.Cys335Arg)

HGVS:

NC_000003.12:g.38606806A>G
NG_008934.1:g.47867T>C
NM_000335.5:c.1003T>CMANE SELECT
NM_001099404.2:c.1003T>C
NM_001099405.2:c.1003T>C
NM_001160160.2:c.1003T>C
NM_001160161.2:c.1003T>C
NM_001354701.2:c.1003T>C
NM_198056.3:c.1003T>C
NP_000326.2:p.Cys335Arg
NP_001092874.1:p.Cys335Arg
NP_001092875.1:p.Cys335Arg
NP_001153632.1:p.Cys335Arg
NP_001153633.1:p.Cys335Arg
NP_001341630.1:p.Cys335Arg
NP_932173.1:p.Cys335Arg
LRG_289t1:c.1003T>C
LRG_289:g.47867T>C
NC_000003.11:g.38648297A>G
NM_198056.2:c.1003T>C

Protein change:

C335R

Links:

dbSNP: rs2125906059

NCBI 1000 Genomes Browser:

rs2125906059

Molecular consequence:

NM_000335.5:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.1003T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001574946	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 6, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25650408, 30193851, 28781330, 29402340, 28492532
SCV001986390	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 9, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574946

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 6, 2022)

germline

clinical testing

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

SCV001986390

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 9, 2019)

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome.

Le Scouarnec S, Karakachoff M, Gourraud JB, Lindenbaum P, Bonnaud S, Portero V, Duboscq-Bidot L, Daumy X, Simonet F, Teusan R, Baron E, Violleau J, Persyn E, Bellanger L, Barc J, Chatel S, Martins R, Mabo P, Sacher F, Haïssaguerre M, Kyndt F, Schmitt S, et al.

Hum Mol Genet. 2015 May 15;24(10):2757-63. doi: 10.1093/hmg/ddv036. Epub 2015 Feb 3.

PubMed [citation]

PMID:: 25650408

Clinical presentation and follow-up of women affected by Brugada syndrome.

Berthome P, Tixier R, Briand J, Geoffroy O, Babuty D, Mansourati J, Jesel L, Dupuis JM, Bru P, Kyndt F, Guyomarch B, Thollet A, Behar N, Mabo P, Sacher F, Probst V, Gourraud JB.

Heart Rhythm. 2019 Feb;16(2):260-267. doi: 10.1016/j.hrthm.2018.08.032. Epub 2018 Sep 5.

PubMed [citation]

PMID:: 30193851

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001574946.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys335 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 25650408, 30193851), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt SCN5A protein function. ClinVar contains an entry for this variant (Variation ID: 1066556). This missense change has been observed in individuals with clinical features of Brugada syndrome (PMID: 28781330, 29402340; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 335 of the SCN5A protein (p.Cys335Arg).

#	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, SCV001986390.2

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

Description

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28781330, 29402340, 32533946, 33131149)

#	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: Oct 8, 2024

ClinVar

Relating variation to medicine