VCV000067978.29 - ClinVar

NM_000335.5(SCN5A):c.52C>T (p.Arg18Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(16)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(2); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000335.5(SCN5A):c.52C>T (p.Arg18Trp)

Variation ID: 67978 Accession: VCV000067978.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38633256 (GRCh38) [ NCBI UCSC ] 3: 38674747 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 6, 2015	May 1, 2024	Jan 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.52C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Arg18Trp	missense
NM_001099404.2:c.52C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Arg18Trp	missense
NM_001099405.2:c.52C>T	NP_001092875.1:p.Arg18Trp	missense
NM_001160160.2:c.52C>T	NP_001153632.1:p.Arg18Trp	missense
NM_001160161.2:c.52C>T	NP_001153633.1:p.Arg18Trp	missense
NM_001354701.2:c.52C>T	NP_001341630.1:p.Arg18Trp	missense
NM_198056.3:c.52C>T	NP_932173.1:p.Arg18Trp	missense
NC_000003.12:g.38633256G>A
NC_000003.11:g.38674747G>A
NG_008934.1:g.21417C>T
LRG_289:g.21417C>T
LRG_289t1:c.52C>T	LRG_289p1:p.Arg18Trp
	Q14524:p.Arg18Trp

... more HGVS ... less HGVS

Protein change

R18W

Other names

p.R18W:CGG>TGG

Canonical SPDI

NC_000003.12:38633255:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00007

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00027

Exome Aggregation Consortium (ExAC) 0.00033

Links

ClinGen: CA019099 UniProtKB: Q14524#VAR_068325 dbSNP: rs199473044 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN5A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3783	4224

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 17, 2024	RCV000058764.19
not specified	Uncertain significance (2)	criteria provided, single submitter	Apr 25, 2016	RCV000212988.13
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	May 27, 2021	RCV000619162.11
Progressive familial heart block, type 1A	Uncertain significance (1)	criteria provided, single submitter	May 8, 2019	RCV001146623.12
Sick sinus syndrome 1	Uncertain significance (1)	criteria provided, single submitter	May 8, 2019	RCV001146621.12
Ventricular fibrillation, paroxysmal familial, type 1	Uncertain significance (1)	criteria provided, single submitter	May 8, 2019	RCV001146624.12
Long QT syndrome 3	Uncertain significance (1)	criteria provided, single submitter	May 8, 2019	RCV001146625.12
Catecholaminergic polymorphic ventricular tachycardia 1	Uncertain significance (1)	no assertion criteria provided	Oct 14, 2014	RCV000157474.10
Cardiac arrhythmia	Likely benign (1)	criteria provided, single submitter	Oct 20, 2018	RCV001842382.10
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 18, 2017	RCV000623091.11
Brugada syndrome 1	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 22, 2023	RCV000987246.15
Dilated cardiomyopathy 1E	Uncertain significance (1)	criteria provided, single submitter	May 8, 2019	RCV001146622.12
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 25, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540277.1 First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.2% (32/16508) South Asian (less) Method: Genome/Exome Filtration
Uncertain significance (Jul 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial isolated arrhythmogenic right ventricular dysplasia Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000740427.1 First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018
Uncertain significance (May 08, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1E Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001307374.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (May 08, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001307372.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 20129283 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (May 08, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Sick sinus syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001307373.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (May 08, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Progressive familial heart block, type 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001307375.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (May 08, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ventricular fibrillation, paroxysmal familial, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001307376.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (May 08, 2019)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Long QT syndrome 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001307377.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 15840476 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001136496.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023
Likely benign (Jan 17, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000557143.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024
Benign (May 27, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000738183.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 15840476‚ 19841300‚ 20129283‚ 23805106‚ 25351510‚ 25904541‚ 28600387‚ 32048431 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Oct 20, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000913714.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Aug 27, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000235313.13 First in ClinVar: Jul 05, 2015 Last updated: Jul 15, 2021	Comment: This variant is associated with the following publications: (PMID: 32048431, 28988457, 28600387, 25904541, 20129283, 15840476, 25351510, 19862833, 23805106, 29728395)
Benign (Jul 18, 2011)	no assertion criteria provided Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280477.1 First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016	Comment: 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 … (more) 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.Arg18Trp (c.52C>T) in the SCN5A gene Given the frequency in ancestry-matched unselected individuals and the very weak case data we consider this variant to be likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Tester et al (2005) observed the variant in 1 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). The variant was reported online in 39 of 59,815 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 21, 2015). The highest frequency was in 32 of 8254. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. (less) Number of individuals with the variant: 2
Uncertain significance (Oct 14, 2014)	no assertion criteria provided Method: clinical testing	Catecholaminergic polymorphic ventricular tachycardia Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207219.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015 Comment: Found together with likely pathogenic PLN:NM_002667.3:c.116T>G	Publications: PubMed (3) PubMed: 15840476‚ 20129283‚ 19841300 Number of individuals with the variant: 1
not provided (-)	no classification provided Method: literature only	not provided Affected status: unknown Allele origin: germline	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust Accession: SCV000090284.3 First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016	Publications: PubMed (4) PubMed: 22581653‚ 15840476‚ 19841300‚ 20129283 Comment: This variant has been reported in the following publications (PMID:15840476;PMID:19841300;PMID:20129283).
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Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.2% (32/16508) South Asian

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

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.Arg18Trp (c.52C>T) in the SCN5A gene Given the frequency in ancestry-matched unselected individuals and the very weak case data we consider this variant to be likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Tester et al (2005) observed the variant in 1 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). The variant was reported online in 39 of 59,815 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 21, 2015). The highest frequency was in 32 of 8254. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes.	Diebold I	Human mutation	2020	PMID: 32048431
Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry).	Mellor G	Circulation. Cardiovascular genetics	2017	PMID: 28600387
Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel.	Kapplinger JD	Circulation. Cardiovascular genetics	2015	PMID: 25904541
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Characterization of N-terminally mutated cardiac Na(+) channels associated with long QT syndrome 3 and Brugada syndrome.	Gütter C	Frontiers in physiology	2013	PMID: 23805106
An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.	Kapplinger JD	Heart rhythm	2010	PMID: 20129283
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.	Kapa S	Circulation	2009	PMID: 19841300
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.	Tester DJ	Heart rhythm	2005	PMID: 15840476

Text-mined citations for rs199473044 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.52C>T (p.Arg18Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199473044 ...