NM_000335.5(SCN5A):c.5686C>T (p.Arg1896Trp) AND not provided

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Aug 5, 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:: RCV000058797.35

Allele description [Variation Report for NM_000335.5(SCN5A):c.5686C>T (p.Arg1896Trp)]

NM_000335.5(SCN5A):c.5686C>T (p.Arg1896Trp)

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.5686C>T (p.Arg1896Trp)

Other names:

p.R1897W:CGG>TGG

HGVS:

NC_000003.12:g.38550683G>A
NG_008934.1:g.103990C>T
NM_000335.5:c.5686C>TMANE SELECT
NM_001099404.2:c.5689C>T
NM_001099405.2:c.5635C>T
NM_001160160.2:c.5590C>T
NM_001160161.2:c.5527C>T
NM_001354701.2:c.5632C>T
NM_198056.3:c.5689C>T
NP_000326.2:p.Arg1896Trp
NP_000326.2:p.Arg1896Trp
NP_001092874.1:p.Arg1897Trp
NP_001092875.1:p.Arg1879Trp
NP_001153632.1:p.Arg1864Trp
NP_001153633.1:p.Arg1843Trp
NP_001341630.1:p.Arg1878Trp
NP_932173.1:p.Arg1897Trp
NP_932173.1:p.Arg1897Trp
LRG_289t1:c.5689C>T
LRG_289t2:c.5686C>T
LRG_289:g.103990C>T
LRG_289p1:p.Arg1897Trp
LRG_289p2:p.Arg1896Trp
NC_000003.11:g.38592174G>A
NM_000335.4:c.5686C>T
NM_198056.2:c.5689C>T
p.Arg1897Trp

Protein change:

R1843W

Links:

dbSNP: rs45465995

NCBI 1000 Genomes Browser:

rs45465995

Molecular consequence:

NM_000335.5:c.5686C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5689C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5635C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5590C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5527C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5632C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5689C>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
SCV000090317	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 19716085, 20981092, 22685113, 22581653
SCV000235542	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Aug 5, 2024)	germline	clinical testing	Citation Link,
SCV000291823	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 14, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19716085, 28074886, 30193851, 34461752, 22685113, 28492532
SCV001477582	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Mar 12, 2020)	germline	clinical testing	Citation Link,
SCV001713279	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 3, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001978454	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001979679	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	1	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

A map of human genome variation from population-scale sequencing.

1000 Genomes Project Consortium., Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA.

Nature. 2010 Oct 28;467(7319):1061-73. doi: 10.1038/nature09534. Erratum in: Nature. 2011 May 26;473(7348):544. Xue, Yali [added]; Cartwright, Reed A [added]; Altshuler, David L [corrected to Altshuler, David]; Kebbel, Andrew [corrected to Keebler, Jonathan]; Koko-Gonzales, Paula [corrected to Kokko-Gonzales, Paula]; Nickerson, Debbie A [corrected to Nickerson, Debo.

PubMed [citation]

PMID:: 20981092
PMCID:: PMC3042601

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]

PMID:: 22581653
PMCID:: PMC4640174

See all PubMed Citations (9)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000090317.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

Description

This variant has been reported in the following publications (PMID:19716085;PMID:20981092;PMID:22685113).

#	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 GeneDx, SCV000235542.16

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

Description

Patch-clamp studies revealed R1897W may impact channel steady-state inactivation; however, other electrophysiological properties were not significantly different from wild-type (PMID: 22685113); 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: 25637381, 26159999, 24144883, 25410959, 28150151, 22581653, 26332594, 22995991, 27332903, 28074886, 26835069, 30669290, 25904541, 34621001, 29759671, 31983221, 22685113, 33071830, 34461752, 29709244, 30193851, 31737537, 35932045, 20981092, 19716085, 37652022)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000291823.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1897 of the SCN5A protein (p.Arg1897Trp). This variant is present in population databases (rs45465995, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 22685113, 28074886, 30193851, 34461752). ClinVar contains an entry for this variant (Variation ID: 68003). 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: 22685113). 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001477582.1

#	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.5689C>T; p.Arg1897Trp variant (rs45465995) is reported in the literature in a few individuals, one affected with long QT syndrome (Kapplinger 2009), one with sudden infant death syndrome (Neubauer 2017), one with unexplained cardiac arrest (Tadros 2017), and one with atrial fibrillation (AF) whose mother also had AF but did not carry the variant (Olesen 2012). This variant is also reported in control individuals, including several with normal QT intervals (Ghouse 2015, Kapplinger 2015). This variant is reported in ClinVar (Variation ID: 68003), and is found in the general population with an overall allele frequency of 0.0082% (23/280692 alleles) in the Genome Aggregation Database. The arginine at codon 1897 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show alterations to the steady-state inactivation potential (Ghouse 2015). Due to conflicting information, the clinical significance of the p.Arg1897Trp variant is uncertain at this time. References: Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Kapplinger JD et al. Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95. Neubauer J et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017 Apr;25(4):404-409. Olesen MS et al. High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation. Circ Cardiovasc Genet. 2012 Aug 1;5(4):450-9. Tadros R et al. Yield and Pitfalls of Ajmaline Testing in the Evaluation of Unexplained Cardiac Arrest and Sudden Unexplained Death: Single-Center Experience With 482 Families. JACC Clin Electrophysiol. 2017 Dec 11;3(12):1400-1408.

#	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, SCV001713279.1

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

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001978454.1

#	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, SCV001979679.1

#	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: Oct 13, 2024

Relating variation to medicine