VCV000406437.9 - ClinVar

NM_000335.5(SCN5A):c.2399G>T (p.Arg800Leu)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000335.5(SCN5A):c.2399G>T (p.Arg800Leu)

Variation ID: 406437 Accession: VCV000406437.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38587437 (GRCh38) [ NCBI UCSC ] 3: 38628928 (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	Oct 10, 2018	Apr 20, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.2399G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Arg800Leu	missense
NM_001099404.2:c.2399G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Arg800Leu	missense
NM_001099405.2:c.2399G>T	NP_001092875.1:p.Arg800Leu	missense
NM_001160160.2:c.2399G>T	NP_001153632.1:p.Arg800Leu	missense
NM_001160161.2:c.2399G>T	NP_001153633.1:p.Arg800Leu	missense
NM_001354701.2:c.2399G>T	NP_001341630.1:p.Arg800Leu	missense
NM_198056.3:c.2399G>T	NP_932173.1:p.Arg800Leu	missense
NC_000003.12:g.38587437C>A
NC_000003.11:g.38628928C>A
NG_008934.1:g.67236G>T
LRG_289:g.67236G>T
LRG_289t1:c.2399G>T	LRG_289p1:p.Arg800Leu

... more HGVS ... less HGVS

Protein change

R800L

Other names

Canonical SPDI

NC_000003.12:38587436:C: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 (T)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA060340 dbSNP: rs566251672 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.
Brugada syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 13, 2021	RCV000458394.12
Cardiac arrhythmia	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV001841357.13

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 (Jul 13, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Brugada syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000545070.4 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (3) PubMed: 28492532‚ 23376825‚ 28412158 Comment: This sequence change replaces arginine with leucine at codon 800 of the SCN5A protein (p.Arg800Leu). The arginine residue is moderately conserved and there is a … (more) This sequence change replaces arginine with leucine at codon 800 of the SCN5A protein (p.Arg800Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs566251672, ExAC 0.002%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23376825, 28412158). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A protein function (PMID: 23376825, 28412158). 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. (less)
Uncertain significance (Aug 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001733891.2 First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 23376825‚ 25351510‚ 28412158 Comment: This missense variant replaces arginine with leucine at codon 800 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces arginine with leucine at codon 800 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant increases late sodium current (PMID: 23376825). This variant has been reported in three individuals affected with long QT syndrome (PMID: 23376825, 28412158) and another individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 1/248516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004829928.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (3) PubMed: 23376825‚ 25351510‚ 28412158 Comment: This missense variant replaces arginine with leucine at codon 800 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces arginine with leucine at codon 800 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant increases late sodium current (PMID: 23376825). This variant has been reported in three individuals affected with long QT syndrome (PMID: 23376825, 28412158) and another individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 1/248516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 3

Comment:

This sequence change replaces arginine with leucine at codon 800 of the SCN5A protein (p.Arg800Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs566251672, ExAC 0.002%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23376825, 28412158). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A protein function (PMID: 23376825, 28412158). 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.

Comment:

This missense variant replaces arginine with leucine at codon 800 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant increases late sodium current (PMID: 23376825). This variant has been reported in three individuals affected with long QT syndrome (PMID: 23376825, 28412158) and another individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 1/248516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Lidocaine attenuation testing: An in vivo investigation of putative LQT3-associated variants in the SCN5A-encoded sodium channel.	Anderson HN	Heart rhythm	2017	PMID: 28412158
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I(Na) contributing to LQT syndrome.	Hu RM	American journal of physiology. Heart and circulatory physiology	2013	PMID: 23376825

Text-mined citations for rs566251672 ...

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.2399G>T (p.Arg800Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs566251672 ...