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

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Nov 4, 2024
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:: RCV000725469.30

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

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_001099404.1:c.3911C>T
NM_198056.2:c.3911C>T

Protein change:

T1250M

Links:

dbSNP: rs199473603

NCBI 1000 Genomes Browser:

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:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
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
SCV000235458	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 4, 2024)	germline	clinical testing	Citation Link,
SCV000337160	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Nov 16, 2015)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10508990, 19716085, 25637381 Citation Link,
SCV000545009	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 31, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10508990, 17210839, 19716085, 19841300, 24631775, 25210526, 28341588, 30847666, 17210841, 28492532
SCV000924952	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Uncertain significance (Mar 31, 2017)	germline	provider interpretation
SCV001160606	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Feb 18, 2020)	germline	clinical testing	Citation Link,
SCV005050815	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2024)	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	unknown	1	not provided	not provided	not provided	not provided	clinical testing, provider interpretation
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations.

Wattanasirichaigoon D, Vesely MR, Duggal P, Levine JC, Blume ED, Wolff GS, Edwards SB, Beggs AH.

Am J Med Genet. 1999 Oct 29;86(5):470-6.

PubMed [citation]

PMID:: 10508990

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000235458.17

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

Description

Reported in individuals with various cardiac phenotypes, including LQTS, Brugada syndrome, lone atrial fibrillation, sudden infant death syndrome, cardiomyopathy, and T-wave inversion (PMID: 17210839, 10508990, 10973849, 19716085, 22685113, 25210526, 23465283, 29764897, 31514951, 34065239); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have been reported and show conflicting results (PMID: 17210841, 24613995); This variant is associated with the following publications: (PMID: 10973849, 19716085, 28316956, 31514951, 30193851, 22685113, 23465283, 22378279, 25637381, 25210526, 10961955, 18503232, 23272275, 24055113, 24613995, 25351510, 25410959, 25904541, 25898860, 27153395, 29247119, 28412158, 28341588, 30677491, 28988457, 31019283, 31043699, 32048431, 30291343, 30847666, 29764897, 26743238, 19841300, 24144883, 24631775, 26746457, 31395126, 34426522, 34065239, 34621001, 34461752, 33772059, 35060774, 30203441, 10508990, 17210839, 29790872, 17210841, 37937776, 36396199, 35534676, 36129056)

#	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 Eurofins Ntd Llc (ga), SCV000337160.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545009.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1304 of the SCN5A protein (p.Thr1304Met). This variant is present in population databases (rs199473603, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 10508990, 17210839, 17210841, 19716085, 19841300, 24631775, 25210526, 28341588, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67835). 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: 17210841). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of 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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924952.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160606.2

#	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; p.Thr1304Met variant (rs199473603) is reported in the literature in individuals affected with long QT syndrome (Kapa 2009, Wattanasirichaigoon 1999) or Brugada syndrome (Kim 2014), which have different mechanisms of pathogenicity. This variant is also reported with conflicting interpretations by multiple laboratories in ClinVar (Variation ID: 67835), and is found in the non-Finnish European population with an allele frequency of 0.031% (40/127748 alleles) in the Genome Aggregation Database. The threonine at codon 1304 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show conflicting effects on channel function (Beyder 2014, Wang 2007). Due to conflicting information, the clinical significance of the p.Thr1304Met variant is uncertain at this time. References: Beyder A et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014 Jun;146(7):1659-1668. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kim G et al. A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia. Korean J Pediatr. 2014 Aug;57(8):374-8. Wang DW et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 Jan 23;115(3):368-76. Wattanasirichaigoon D et al. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV005050815.6

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

Description

SCN5A: PP3

#	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		1	not provided	not provided	not provided

Last Updated: Dec 22, 2024

ClinVar

Relating variation to medicine