NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 4, 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:: RCV000434418.3

Allele description

NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)

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.310C>T (p.Arg104Trp)

HGVS:

NC_000003.12:g.38630393G>A
NG_008934.1:g.24280C>T
NM_000335.5:c.310C>TMANE SELECT
NM_001099404.2:c.310C>T
NM_001099405.2:c.310C>T
NM_001160160.2:c.310C>T
NM_001160161.2:c.310C>T
NM_001354701.2:c.310C>T
NM_198056.3:c.310C>T
NP_000326.2:p.Arg104Trp
NP_001092874.1:p.Arg104Trp
NP_001092875.1:p.Arg104Trp
NP_001153632.1:p.Arg104Trp
NP_001153633.1:p.Arg104Trp
NP_001341630.1:p.Arg104Trp
NP_932173.1:p.Arg104Trp
NP_932173.1:p.Arg104Trp
LRG_289t1:c.310C>T
LRG_289:g.24280C>T
LRG_289p1:p.Arg104Trp
NC_000003.11:g.38671884G>A
NM_198056.2:c.310C>T
Q14524:p.Arg104Trp

Protein change:

R104W

Links:

UniProtKB: Q14524#VAR_074319; dbSNP: rs199473055

NCBI 1000 Genomes Browser:

rs199473055

Molecular consequence:

NM_000335.5:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000518408	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Apr 21, 2021)	germline	clinical testing	Citation Link,
SCV002292504	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 30193851, 22739120, 34122134, 11960580, 19716085, 20129283, 23321620, 24136861, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000518408

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Apr 21, 2021)

germline

clinical testing

Citation Link,

SCV002292504

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

germline

clinical testing

PubMed (9)
[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

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

Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Na(v)1.5 α-subunits.

Clatot J, Ziyadeh-Isleem A, Maugenre S, Denjoy I, Liu H, Dilanian G, Hatem SN, Deschênes I, Coulombe A, Guicheney P, Neyroud N.

Cardiovasc Res. 2012 Oct 1;96(1):53-63. doi: 10.1093/cvr/cvs211. Epub 2012 Jun 27.

PubMed [citation]

PMID:: 22739120
PMCID:: PMC3444234

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000518408.4

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

Description

Has been reported in individuals with Brugada syndrome (Kapplinger et al., 2010; Clatot et al., 2012); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant eliminates the sodium current and exerts a dominant-negative effect on the wild type channels (Clatot et al., 2012; Wang et al., 2020); Reported in ClinVar as pathogenic (ClinVar Variant ID# 67778; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23874304, 30662450, 30232268, 24136861, 22739120, 23805106, 20129283, 22581653, 26907222, 22871588, 30193851, 30476647, 32815768, 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

From Invitae, SCV002292504.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 104 of the SCN5A protein (p.Arg104Trp). This variant is present in population databases (rs199473055, gnomAD 0.004%). This missense change has been observed in individuals with Brugada syndrome (PMID: 22739120, 30193851). ClinVar contains an entry for this variant (Variation ID: 67778). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 22739120, 34122134). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg104 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11960580, 19716085, 20129283, 23321620, 24136861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: May 19, 2024

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