VCV000067790.12 - ClinVar

NM_000335.5(SCN5A):c.3316G>A (p.Glu1106Lys)

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.

(6)

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(3); Likely benign(2)

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.3316G>A (p.Glu1106Lys)

Variation ID: 67790 Accession: VCV000067790.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38579405 (GRCh38) [ NCBI UCSC ] 3: 38620896 (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 9, 2016	Apr 20, 2024	Jan 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.3316G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Glu1106Lys	missense
NM_001099404.2:c.3319G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Glu1107Lys	missense
NM_001099405.2:c.3319G>A	NP_001092875.1:p.Glu1107Lys	missense
NM_001160160.2:c.3316G>A	NP_001153632.1:p.Glu1106Lys	missense
NM_001160161.2:c.3228+1526G>A		intron variant
NM_001354701.2:c.3316G>A	NP_001341630.1:p.Glu1106Lys	missense
NM_198056.3:c.3319G>A	NP_932173.1:p.Glu1107Lys	missense
NC_000003.12:g.38579405C>T
NC_000003.11:g.38620896C>T
NG_008934.1:g.75268G>A
NG_053884.1:g.1144C>T
LRG_289:g.75268G>A
LRG_289t1:c.3319G>A	LRG_289p1:p.Glu1107Lys

... more HGVS ... less HGVS

Protein change

E1106K, E1107K

Other names

Canonical SPDI

NC_000003.12:38579404:C:T

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.

0.00040 (T)

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

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00013

Exome Aggregation Consortium (ExAC) 0.00018

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

Links

ClinGen: CA017032 dbSNP: rs199473193 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	3791	4234
LOC110121269	-	-	-	GRCh38	-	423

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 28, 2024	RCV000058564.10
Brugada syndrome 1	Uncertain significance (1)	criteria provided, single submitter	May 28, 2019	RCV000987210.1
Cardiac arrhythmia	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV003591670.3

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 (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136459.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Sep 05, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001814133.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: This variant is associated with the following publications: (PMID: 31043699, 22581653, 20129283, 16453024, 19841300)
Likely benign (Jan 28, 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: SCV001049848.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
Uncertain significance (May 01, 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: SCV004361659.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 16453024‚ 19841300‚ 20129283‚ 32449611 Comment: This missense variant replaces glutamic acid with lysine at codon 1107 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant … (more) This missense variant replaces glutamic acid with lysine at codon 1107 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with sudden unexpected death in pediatrics (PMID: 16453024, 32449611), as well as in two healthy Asian control individuals (PMID: 19841300, 20129283). This variant has been identified in 33/244554 chromosomes ( 31/30138 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for SCN5A-related disorders, 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 (Nov 30, 2023)	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: SCV004824939.1 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 (4) PubMed: 16453024‚ 19841300‚ 20129283‚ 32449611 Comment: This missense variant replaces glutamic acid with lysine at codon 1107 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant … (more) This missense variant replaces glutamic acid with lysine at codon 1107 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with sudden unexpected death in pediatrics (PMID: 16453024, 32449611), as well as in two healthy Asian control individuals (PMID: 19841300, 20129283). This variant has been identified in 33/244554 chromosomes ( 31/30138 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for SCN5A-related disorders, 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: 2
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: SCV000090084.3 First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016	Publications: PubMed (4) PubMed: 22581653‚ 19841300‚ 16453024‚ 20129283 Comment: This variant has been reported in the following publications (PMID:19841300;PMID:16453024;PMID:20129283).

Comment:

This missense variant replaces glutamic acid with lysine at codon 1107 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with sudden unexpected death in pediatrics (PMID: 16453024, 32449611), as well as in two healthy Asian control individuals (PMID: 19841300, 20129283). This variant has been identified in 33/244554 chromosomes ( 31/30138 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for SCN5A-related disorders, 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
The role of sodium channels in sudden unexpected death in pediatrics.	Rochtus AM	Molecular genetics & genomic medicine	2020	PMID: 32449611
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
A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.	Plant LD	The Journal of clinical investigation	2006	PMID: 16453024

Text-mined citations for rs199473193 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.3316G>A (p.Glu1106Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199473193 ...