NM_000335.5(SCN5A):c.2944T>C (p.Cys982Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (8 submissions)
Last evaluated:: Jan 15, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000724184.29

Allele description

NM_000335.5(SCN5A):c.2944T>C (p.Cys982Arg)

Genes:

LOC110121269:VISTA enhancer hs2177 [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.2944T>C (p.Cys982Arg)

Other names:

p.C982R:TGT>CGT

HGVS:

NC_000003.12:g.38581215A>G
NG_008934.1:g.73458T>C
NG_053884.1:g.2954A>G
NM_000335.5:c.2944T>CMANE SELECT
NM_001099404.1:c.2944T>C
NM_001099404.2:c.2944T>C
NM_001099405.2:c.2944T>C
NM_001160160.2:c.2944T>C
NM_001160161.2:c.2944T>C
NM_001354701.2:c.2944T>C
NM_198056.3:c.2944T>C
NP_000326.2:p.Cys982Arg
NP_000326.2:p.Cys982Arg
NP_001092874.1:p.Cys982Arg
NP_001092875.1:p.Cys982Arg
NP_001153632.1:p.Cys982Arg
NP_001153633.1:p.Cys982Arg
NP_001341630.1:p.Cys982Arg
NP_932173.1:p.Cys982Arg
NP_932173.1:p.Cys982Arg
LRG_289t1:c.2944T>C
LRG_289t2:c.2944T>C
LRG_289t3:c.2944T>C
LRG_289:g.73458T>C
LRG_289p1:p.Cys982Arg
LRG_289p2:p.Cys982Arg
NC_000003.11:g.38622706A>G
NM_000335.4:c.2944T>C
NM_198056.2:c.2944T>C

Protein change:

C982R

Links:

dbSNP: rs199473182

NCBI 1000 Genomes Browser:

rs199473182

Molecular consequence:

NM_000335.5:c.2944T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2944T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2944T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2944T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2944T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2944T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2944T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Megalobrama amblycephala fibroblast growth factor 1a (fgf1a), mRNA
PREDICTED: Megalobrama amblycephala fibroblast growth factor 1a (fgf1a), mRNA
gi|2238840494|ref|XM_048177069.1|

Nucleotide
Uncultured Mycoplasma sp. clone ME154 16S ribosomal RNA gene, partial sequence
Uncultured Mycoplasma sp. clone ME154 16S ribosomal RNA gene, partial sequence
gi|134140720|gb|DQ917898.1|

Nucleotide
Mus musculus heat shock protein 12A, mRNA (cDNA clone MGC:40846 IMAGE:5369051), ...
Mus musculus heat shock protein 12A, mRNA (cDNA clone MGC:40846 IMAGE:5369051), complete cds
gi|20988479|gb|BC030362.1|

Nucleotide
Erythritol
Erythritol
A four-carbon sugar that is found in algae, fungi, and lichens. It is twice as sweet as sucrose and can be used as a coronary vasodilator.<br/>Year introduced: 1973(1965)

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000226704	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Aug 1, 2014)	germline	clinical testing	Citation Link,
SCV000235424	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 9, 2024)	germline	clinical testing	Citation Link,
SCV000545092	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 15, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001472007	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jul 21, 2020)	germline	clinical testing	Citation Link,
SCV001742584	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001923267	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
SCV001954095	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
SCV001973044	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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

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

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

Details of each submission

From Eurofins Ntd Llc (ga), SCV000226704.5

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000235424.17

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20102864, 19841300, 24055113, 25637381, 25351510, 27000522, 22581653, 26746457, 32880476, 16712702, 25904541, 19862833)

#	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, SCV000545092.9

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001472007.1

#	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.2944T>C, p.Cys982Arg variant (rs199473182), has been reported in multiple individuals selected for cardiac arrhythmia (Hofman-Bang 2006), sudden cardiac death (Cann 2017), or actionable variants in genomic medicine studies (Amendola 2015 and Dorschner 2013). This variant has been submitted to the ClinVar database (Variation ID: 67769). It is found in the African population with an allele frequency of 0.08% (18/23,286 alleles) in the Genome Aggregation Database. The cysteine at codon 982 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Cys982Arg variant is uncertain at this time. References: Amendola et al. Actionable Exomic Incidental Findings in 6503 Participants: Challenges of Variant Classification. Genome Res. 2015 Mar. Cann et al. Phenotype-driven Molecular Autopsy for Sudden Cardiac Death. Clin Genet. 2017 Jan. Dorschner et al. Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes. Am J Hum Genet. 2013 Oct 3. Hofman-Bang et al. High-efficiency Multiplex Capillary Electrophoresis Single Strand Conformation Polymorphism (multi-CE-SSCP) Mutation Screening of SCN5A: A Rapid Genetic Approach to Cardiac Arrhythmia. Clin Genet. 2006 Jun. Gene statement: Pathogenic germline variants in the SCN5A gene are inherited in an autosomal dominant manner and are associated with dilated cardiomyopathy 1E (MIM: 601154), familial atrial fibrillation 10 (MIM: 614022), Brugada syndrome 1 (MIM: 601144), nonprogressive heart block and progressive heart block 1A (MIM: 113900), Long QT syndrome-3 (MIM: 603830), familial ventricular fibrillation (MIM: 603829), and, more rarely, autosomal recessive sick sinus syndrome-1 (MIM: 608567).

#	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, SCV001742584.3

#	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, SCV001923267.1

#	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, SCV001954095.1

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001973044.1

#	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: Sep 16, 2024

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