NM_000335.5(SCN5A):c.3401G>T (p.Ser1134Ile) AND not provided

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Sep 8, 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:: RCV000183035.18

Allele description [Variation Report for NM_000335.5(SCN5A):c.3401G>T (p.Ser1134Ile)]

NM_000335.5(SCN5A):c.3401G>T (p.Ser1134Ile)

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.3401G>T (p.Ser1134Ile)

Other names:

p.S1135I:AGT>ATT

HGVS:

NC_000003.12:g.38576768C>A
NG_008934.1:g.77905G>T
NM_000335.5:c.3401G>TMANE SELECT
NM_001099404.2:c.3404G>T
NM_001099405.2:c.3404G>T
NM_001160160.2:c.3401G>T
NM_001160161.2:c.3242G>T
NM_001354701.2:c.3401G>T
NM_198056.3:c.3404G>T
NP_000326.2:p.Ser1134Ile
NP_001092874.1:p.Ser1135Ile
NP_001092875.1:p.Ser1135Ile
NP_001153632.1:p.Ser1134Ile
NP_001153633.1:p.Ser1081Ile
NP_001341630.1:p.Ser1134Ile
NP_932173.1:p.Ser1135Ile
NP_932173.1:p.Ser1135Ile
LRG_289t1:c.3404G>T
LRG_289:g.77905G>T
LRG_289p1:p.Ser1135Ile
NC_000003.11:g.38618259C>A
NM_198056.2:c.3404G>T

Protein change:

S1081I

Links:

dbSNP: rs557957405

NCBI 1000 Genomes Browser:

rs557957405

Molecular consequence:

NM_000335.5:c.3401G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3404G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3404G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3401G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3242G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3401G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3404G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000235443	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 27, 2023)	germline	clinical testing	Citation Link,
SCV001497375	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24667783, 30847666, 28492532
SCV001739868	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001921885	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001930293	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001979619	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing

Help

Summary from all submissions

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

Citations

PubMed

Genetic analysis, in silico prediction, and family segregation in long QT syndrome.

Riuró H, Campuzano O, Berne P, Arbelo E, Iglesias A, Pérez-Serra A, Coll-Vidal M, Partemi S, Mademont-Soler I, Picó F, Allegue C, Oliva A, Gerstenfeld E, Sarquella-Brugada G, Castro-Urda V, Fernández-Lozano I, Mont L, Brugada J, Scornik FS, Brugada R.

Eur J Hum Genet. 2015 Jan;23(1):79-85. doi: 10.1038/ejhg.2014.54. Epub 2014 Mar 26.

PubMed [citation]

PMID:: 24667783
PMCID:: PMC4266740

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

van Lint FHM, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH, Christiaans I.

Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.

PubMed [citation]

PMID:: 30847666
PMCID:: PMC6533346

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000235443.12

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

Description

Identified in association with LQTS, Brugada syndrome, and unspecified arrhythmia in published literature (Riuro et al., 2015; van Lint et al., 2019; Walsh et al., 2021); Identified in a patient with myxomatous mitral valve disease and flail posterior leaflet who suffered sudden cardiac death while being treated with azithromycin (Missov et al., 2015); this patient also harbored a variant in the DSP gene; 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: 30847666, 32893267, 32009526, 24667783, 26071830)

#	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 Invitae, SCV001497375.3

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

Description

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1135 of the SCN5A protein (p.Ser1135Ile). 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. 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. ClinVar contains an entry for this variant (Variation ID: 201494). This missense change has been observed in individual(s) with long QT syndrome and arrhythmia (PMID: 24667783, 30847666). This variant is present in population databases (rs557957405, gnomAD 0.007%).

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001739868.3

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

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001921885.1

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

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001930293.1

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

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001979619.1

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

#	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

Last Updated: Jun 9, 2024

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