NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met) AND SCN5A-related disorder

Germline classification:: Uncertain significance (2 submissions)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004537261.4

Allele description [Variation Report for NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)]

NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)

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.3908C>T (p.Thr1303Met)

Other names:

p.T1304M:ACG>ATG; Thr1304Met; p.(Thr1303Met)

HGVS:

NC_000003.12:g.38562467G>A
NG_008934.1:g.92206C>T
NM_000335.5:c.3908C>TMANE SELECT
NM_001099404.2:c.3911C>T
NM_001099405.2:c.3911C>T
NM_001160160.2:c.3908C>T
NM_001160161.2:c.3749C>T
NM_001354701.2:c.3908C>T
NM_198056.3:c.3911C>T
NP_000326.2:p.Thr1303Met
NP_000326.2:p.Thr1303Met
NP_001092874.1:p.Thr1304Met
NP_001092874.1:p.Thr1304Met
NP_001092875.1:p.Thr1304Met
NP_001153632.1:p.Thr1303Met
NP_001153633.1:p.Thr1250Met
NP_001341630.1:p.Thr1303Met
NP_932173.1:p.Thr1304Met
NP_932173.1:p.Thr1304Met
LRG_289t1:c.3911C>T
LRG_289t2:c.3908C>T
LRG_289t3:c.3911C>T
LRG_289:g.92206C>T
LRG_289p1:p.Thr1304Met
LRG_289p2:p.Thr1303Met
LRG_289p3:p.Thr1304Met
NC_000003.11:g.38603958G>A
NM_000335.4:c.3908C>T
NM_000335.5:c.3908C>T
NM_001099404.1:c.3911C>T
NM_198056.2:c.3911C>T

Protein change:

T1250M

Links:

dbSNP: rs199473603

Molecular consequence:

NM_000335.5:c.3908C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3911C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3911C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3908C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3749C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3908C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3911C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: SCN5A-related disorder
Synonyms:: SCN5A-related disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004754871	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Uncertain significance (Apr 1, 2024)	germline	clinical testing
SCV006555392	Daryl Scott Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004754871

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Uncertain significance
(Apr 1, 2024)

germline

clinical testing

SCV006555392

Daryl Scott Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004754871.2

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

Description

The SCN5A c.3911C>T variant is predicted to result in the amino acid substitution p.Thr1304Met. This variant was reported in individuals with long QT syndrome and Brugada syndrome (Wattanasirichaigoon et al. 1999. PMID: 10508990; Arnestad et al. 2007. PMID: 17210839; Kapplinger et al. 2009. PMID: 19716085; Kapa et al. 2009. PMID: 19841300; Table SVI, Milman et al. 2021. PubMed ID: 34461752). Functional studies showed conflicting evidences of pathogenicity for this variant. Although one study suggested this variant significantly increased persistent sodium currents and faster recovery from inactivation (Wang et al. 2007. PMID: 17210841), another demonstrated no difference from wild type SCN5A (Beyder et al. 2014. PubMed ID: 24613995). This variant also had conflicting interpretations of pathogenicity in the literature ranging from benign to pathogenic (Table S1, Amendola et al. 2015. PMID: 25637381; Table S1, Paludan-Müller et al. 2019. PubMed ID: 31043699; Table SVI, Milman et al. 2021. PubMed ID: 34461752). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, uncertain significance, likely pathogenic, and pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/67835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#	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 Daryl Scott Lab, Baylor College of Medicine, SCV006555392.1

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

Description

BS2, BP5, PS3_supporting, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jul 14, 2026

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