NM_000335.5(SCN5A):c.5708C>T (p.Ser1903Leu) AND not specified

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Feb 10, 2025
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:: RCV000041630.22

Allele description [Variation Report for NM_000335.5(SCN5A):c.5708C>T (p.Ser1903Leu)]

NM_000335.5(SCN5A):c.5708C>T (p.Ser1903Leu)

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.5708C>T (p.Ser1903Leu)

Other names:

p.S1904L:TCG>TTG

HGVS:

NC_000003.12:g.38550661G>A
NG_008934.1:g.104012C>T
NM_000335.5:c.5708C>TMANE SELECT
NM_001099404.2:c.5711C>T
NM_001099405.2:c.5657C>T
NM_001160160.2:c.5612C>T
NM_001160161.2:c.5549C>T
NM_001354701.2:c.5654C>T
NM_198056.3:c.5711C>T
NP_000326.2:p.Ser1903Leu
NP_000326.2:p.Ser1903Leu
NP_001092874.1:p.Ser1904Leu
NP_001092875.1:p.Ser1886Leu
NP_001153632.1:p.Ser1871Leu
NP_001153633.1:p.Ser1850Leu
NP_001341630.1:p.Ser1885Leu
NP_932173.1:p.Ser1904Leu
NP_932173.1:p.Ser1904Leu
LRG_289t1:c.5711C>T
LRG_289t2:c.5708C>T
LRG_289:g.104012C>T
LRG_289p1:p.Ser1904Leu
LRG_289p2:p.Ser1903Leu
NC_000003.11:g.38592152G>A
NM_000335.4:c.5708C>T
NM_198056.2:c.5711C>T
c.5711C>T

Protein change:

S1850L

Links:

dbSNP: rs150264233

Molecular consequence:

NM_000335.5:c.5708C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5711C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5657C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5612C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5549C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5654C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5711C>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
SCV000065326	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Aug 5, 2020)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 18708744, 20129283, 22426227, 22378279, 27435932, 26159999, 25637381, 26332594, 24055113, 28988457, 25904541, 24033266
SCV001338525	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Feb 10, 2025)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 20129283, 22378279, 24055113, 25904541, 18708744, 21167176, 22426227, 24892747, 26332594, 27435932, 26746457, 30153324, 30847666, 34021086 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000065326

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Aug 5, 2020)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001338525

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Feb 10, 2025)

germline

clinical testing

PubMed (14)
[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	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval.

Ghouse J, Have CT, Weeke P, Bille Nielsen J, Ahlberg G, Balslev-Harder M, Appel EV, Skaaby T, Olesen SP, Grarup N, Linneberg A, Pedersen O, Haunsø S, Hastrup Svendsen J, Hansen T, Kanters JK, Salling Olesen M.

Eur Heart J. 2015 Oct 1;36(37):2523-9. doi: 10.1093/eurheartj/ehv297. Epub 2015 Jul 9.

PubMed [citation]

PMID:: 26159999

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

See all PubMed Citations (18)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000065326.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (12)

Description

The p.Ser1904Leu variant in SCN5A has been reported in several individuals with a range of cardiac manifestations (Bankston 2007 PMID: 18708744, Kapplinger 2010 PMID: 20129283, Methner 2016 PMID: 27435932, LMM data). However, this variant has also been identified in 0.17% (42/24204) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is inconsistent with the reported prevalence of SCN5A-associated disease. This variant has also been reported in ClinVar (Variation ID: 48310). Computational prediction tools and conservation analyses predict an impact to the protein and in vitro studies suggest that the p.Ser1904Leu variant may impact protein function (Bankston 2007 PMID: 18708744, Glaaser 2012 PMID: 22426227, Kapplinger 2010 PMID: 20129283). However, this in vitro assay may not accurately represent biological function. In summary, because of the frequency, this variant is classified as likely benign. ACMG/AMP Criteria applied: PP3, PS4_Supporting, BS1.

#	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		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338525.3

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

Description

Variant summary: SCN5A c.5711C>T (p.Ser1904Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 283812 control chromosomes (gnomAD, Bankston_2007, Kapplinger_2010, Kapplinger_2015), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 68 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.5711C>T has been reported in at least one individual with LQTS and segregated with symptoms of disease in two family members, however only a subset of LQTS-associated genes were sequenced in these individuals (Bankston_2007). In addition, the variant has been reported in at least one individual affected with SIDS (Methner_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Several publications report experimental evidence evaluating an impact on protein function. These studies report that the variant disrupts sodium channel gate inactivation and promotes late Na+ channel currents by increasing the propensity of the channel to reopen during prolonged depolarization (Bankston_2007, Glaaser_2012). Another study reports that the variant may have a more severe electrophysiological impact in certain tissue types, as the effect in Purkinje fiber cells was more significant than that observed in a ventricular myocyte model (Iyer_2014). A recent study showed that the variant had had reduced affinity for Calmodulin binding compared to wildtype (Kang_2021). These in-vitro studies do not allow convincing conclusions about the variant effect, however, as the variant does not appear to alter the overall function of the sodium channels and it is unclear how these findings would translate in-vivo. The following publications have been ascertained in the context of this evaluation (PMID: 18708744, 21167176, 24055113, 22426227, 30153324, 24892747, 34021086, 25904541, 20129283, 27435932, 26332594, 22378279, 26746457, 30847666). ClinVar contains an entry for this variant (Variation ID: 48310). Based on the evidence outlined above, the variant was classified as likely benign.

#	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: Apr 12, 2026

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