NM_000335.5(SCN5A):c.5126C>T (p.Ser1709Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 30, 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:: RCV000183102.18

Allele description [Variation Report for NM_000335.5(SCN5A):c.5126C>T (p.Ser1709Leu)]

NM_000335.5(SCN5A):c.5126C>T (p.Ser1709Leu)

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.5126C>T (p.Ser1709Leu)

Other names:

p.S1710L:TCG>TTG; p.Ser1710Leu

HGVS:

NC_000003.12:g.38551243G>A
NG_008934.1:g.103430C>T
NM_000335.5:c.5126C>TMANE SELECT
NM_001099404.2:c.5129C>T
NM_001099405.2:c.5075C>T
NM_001160160.2:c.5030C>T
NM_001160161.2:c.4967C>T
NM_001354701.2:c.5072C>T
NM_198056.3:c.5129C>T
NP_000326.2:p.Ser1709Leu
NP_001092874.1:p.Ser1710Leu
NP_001092874.1:p.Ser1710Leu
NP_001092875.1:p.Ser1692Leu
NP_001153632.1:p.Ser1677Leu
NP_001153633.1:p.Ser1656Leu
NP_001341630.1:p.Ser1691Leu
NP_932173.1:p.Ser1710Leu
NP_932173.1:p.Ser1710Leu
LRG_289t1:c.5129C>T
LRG_289t3:c.5129C>T
LRG_289:g.103430C>T
LRG_289p1:p.Ser1710Leu
LRG_289p3:p.Ser1710Leu
NC_000003.11:g.38592734G>A
NM_001099404.1:c.5129C>T
NM_198056.2:c.5129C>T

Protein change:

S1656L; SER1710LEU

Links:

OMIM: 600163.0014; dbSNP: rs137854604

NCBI 1000 Genomes Browser:

rs137854604

Molecular consequence:

NM_000335.5:c.5126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5129C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5075C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5030C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.4967C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5072C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5129C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000235512	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 24, 2022)	germline	clinical testing	Citation Link,
SCV000280476	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Likely pathogenic (Jan 14, 2014)	germline	clinical testing
SCV000637172	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14961552, 19026623, 22247482, 23139254, 25326637, 26798387, 10940383, 28492532
SCV004226747	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 11, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 10940383, 11827685, 14961552, 17141278, 19026623, 22247482, 25326637, 26798387, 28152038, 32553838, 33221895, 34649698, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	7	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Integration of genetics into a systems model of electrocardiographic traits using HumanCVD BeadChip.

Gaunt TR, Shah S, Nelson CP, Drenos F, Braund PS, Adeniran I, Folkersen L, Lawlor DA, Casas JP, Amuzu A, Kivimaki M, Whittaker J, Eriksson P, Zhang H, Hancox JC, Tomaszewski M, Burton PR, Tobin MD, Humphries SE, Talmud PJ, Macfarlane PW, Hingorani AD, et al.

Circ Cardiovasc Genet. 2012 Dec;5(6):630-8. doi: 10.1161/CIRCGENETICS.112.962852. Epub 2012 Nov 8.

PubMed [citation]

PMID:: 23139254

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000235512.14

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

Description

Published functional studies demonstrate a damaging effect by causing a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation compared to wildtype (Akai et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14961552, 17141278, 10940383, 22247482, 26798387, 25326637, 23139254, 30975432, 11827685, 17698727, 28150151, 19026623, 32091595, 30609406, 29625023, 28152038, 32553838, 34649698, 33221895)

#	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 Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280476.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1710Leu (S1710L; c.5129 C>T) in the SCN5A gene This variant has been previously observed in five unrelated cases of Brugada syndrome (including one case of idiopathic VF without a strict Brugada diagnosis). No published segregation data is available, but good in-vitro functional data is available. With our 2 cases (both have Mexican ancestry), this makes 7 families. Akai et al. (2000) first reported the variant in a Japanese patient with idiopathic ventricular fibrillation, a history of recurrent syncope, and sudden death in a paternal uncle and paternal grandfather, but no type 1 Brugada pattern on EKG. Shin et al. (2007) reported the variant in a male Korean patient with a type 1 Brugada syndrome pattern on EKG that was unmasked by flecainide and a family history of sudden cardiac death. The testing laboratory reports that Ser1710Leu has also been seen in three additional unrelated individuals tested for Brugada syndrome at their lab (as of January 2014). Functional data is available. The SCN5A gene produces the cardiac sodium channel alpha subunit, and Ser1710 is located in the highly conserved pore-forming linker between segments 5 and 6 in transmembrane domain 4 (Akai et al. 2000; Shin et al. 2007). Functional studies show that Ser1710Leu mutant channels have altered biophysical properties, which may result in diminished sodium current into the myocyte. Akai et al. (2000) and Shirai et al. (2002) showed that mutant channels expressed in human embryonic kidney cells show faster inactivation and current decay, a large hyperpolarizing shift in the voltage-dependent threshold for steady-state inactivation, a positive shift in the voltage-dependent threshold for channel activation, and delayed recovery from inactivation. Variants at nearby residues (within 10 amino acids to either side) have been associated with Brugada syndrome, suggesting the functional importance of this region of the protein. These include Thr1709Arg, Thr1709Met, Thr1709del, Gly1712Ser, Asp1714Gly (inherited arrhythmias database: Molecular Cardiology Laboratories of IRCCS Fondazione Salvatore Maugeri; GeneDx report of HGMD variants). Ser1710Leu is a nonconservative amino acid change from a polar Serine to a nonpolar Leucine. The Serine at codon 1710 is completely conserved across 39 vertebrate species examined. Surrounding residues are also very highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be "probably damaging" (with a maximum score of 1). In total the variant has not been seen in ~6850 individuals from published reports and publicly available population datasets. There is no variation at residue 1710 listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of June 27, 2012. The variant was not observed in published controls: Akai et al. (2000) did not find Ser1710Leu in 150 (Japanese?) controls. Shin et al. (2007) did not detect it in 200 Korean controls. GeneDx did not report controls.

#	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		7	not provided	not provided	not provided

From Invitae, SCV000637172.5

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

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1710 of the SCN5A protein (p.Ser1710Leu). This variant is present in population databases (rs137854604, gnomAD 0.009%). This missense change has been observed in individuals with Brugada syndrome, idiopathic ventricular fibrillation, progressive familial heart block type I, sick sinus syndrome and paroxysmal familial ventricular fibrillation (PMID: 10940383, 14961552, 19026623, 22247482, 23139254, 25326637, 26798387). ClinVar contains an entry for this variant (Variation ID: 9383). 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: 10940383). 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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226747.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

Description

PP3, PM1, PS3_moderate, PS4_moderate

#	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

Last Updated: Jul 23, 2024

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