NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 12, 2026
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:: RCV000824759.18

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]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000710929	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Apr 26, 2018)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 10508990, 25210526, 10961955, 10973849, 17210839, 17210841, 19716085, 22685113, 25410959, 26743238, 18451998, 25904541, 24613995, 24033266
SCV005185790	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 12, 2026)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 19716085, 17210839, 17210841, 10508990, 19841300, 30847666, 36129056, 37937776, 35534676, 36396199, 39486665 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000710929

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Apr 26, 2018)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV005185790

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 12, 2026)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

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	germline	not provided	8	7	not provided	not provided	not provided	clinical testing

Citations

PubMed

A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia.

Kim G, Kyung YC, Kang IS, Song J, Huh J, On YK.

Korean J Pediatr. 2014 Aug;57(8):374-8. doi: 10.3345/kjp.2014.57.8.374. Epub 2014 Aug 25.

PubMed [citation]

PMID:: 25210526
PMCID:: PMC4155183

The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge.

Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E.

Circulation. 2000 Aug 29;102(9):945-7.

PubMed [citation]

PMID:: 10961955

See all PubMed Citations (21)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000710929.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (14)

Description

The p.Thr1304Met variant in SCN5A has been reported in 3 individuals with long Q T syndrome, 1 infant with sudden infant death syndrome, 1 individual with Brugad a syndrome, 1 individual with early-onset atrial fibrillation (Wattanasirichaigo on 1999, Priori 2000, Splawski 2000, Arnestad 2007, Olesen 2012, Kim 2014). This variant segregated with LQTS in 2 affected relatives from 1 family and with Br ugada syndrome in 1 affected relative from 1 family. However, other clinical lab oratories have observed this variant in individuals who carried other disease-ca using variants (GeneDx, Emory, Invitae; personal communication) and this variant has been reported in multiple healthy individuals (Weeke 2015, Kapplinger 2015) . Additionally, it is unclear if the same variant would be causative for such a diverse set of phenotypes, suggesting that it may not have a functional effect. This variant has also been identified in 0.03% (35/126116) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473603). Additionally, in vitro functional studies have shown confli cting results (Want 2007, Makita 2008, Beyder 2014). In summary, due to the pres ence of conflicting data, the clinical significance of the p.Thr1304Met variant is uncertain. ACMG/AMP Criteria applied: PP1; BP5.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		8	not provided	7	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005185790.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: SCN5A c.3911C>T (p.Thr1304Met) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00018 in 247644 control chromosomes. The observed variant frequency exceeds the estimated maximal expected allele frequency for disease-causing variants in SCN5A. c.3911C>T has been observed in individuals affected with Long QT Syndrome and other related conditions (Wattanasirichaigoon_1999, Arnestad_2007, Kapplinger_2009, Kapa_2009, van Lint_2019). These data indicate that the variant may be associated with disease. At least one publication evaluates an impact of this variant on protein function reports experimental evidence that this variant affects protein function (Wang_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17210839, 37937776, 35534676, 19841300, 19716085, 36396199, 17210841, 10508990, 39486665, 36129056, 30847666). ClinVar contains an entry for this variant (Variation ID: 67835). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Jul 14, 2026

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