VCV000190895.46 - ClinVar

NM_174934.4(SCN4B):c.632C>G (p.Thr211Arg)

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.

(9)

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(5); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_174934.4(SCN4B):c.632C>G (p.Thr211Arg)

Variation ID: 190895 Accession: VCV000190895.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 118137082 (GRCh38) [ NCBI UCSC ] 11: 118007797 (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	Mar 8, 2017	Oct 20, 2024	Sep 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_174934.4:c.632C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_777594.1:p.Thr211Arg	missense
NM_001142348.2:c.230C>G	NP_001135820.1:p.Thr77Arg	missense
NM_001142349.2:c.302C>G	NP_001135821.1:p.Thr101Arg	missense
NR_024527.2:n.621C>G		non-coding transcript variant
NC_000011.10:g.118137082G>C
NC_000011.9:g.118007797G>C
NG_011710.1:g.20834C>G
LRG_330:g.20834C>G
LRG_330t1:c.632C>G	LRG_330p1:p.Thr211Arg

... more HGVS ... less HGVS

Protein change

T211R, T101R, T77R

Other names

p.T211R:ACG>AGG

Canonical SPDI

NC_000011.10:118137081:G:C

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00014

Links

ClinGen: CA302222 dbSNP: rs201454653 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.
SCN4B		-	-	GRCh38 GRCh37	251	356

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	Uncertain significance (6)	criteria provided, multiple submitters, no conflicts	Sep 19, 2024	RCV000994731.38
Long QT syndrome 10	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 18, 2023	RCV001227229.14
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Mar 14, 2022	RCV002362871.9

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 (Nov 18, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Long QT syndrome 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001399579.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28837624‚ 30847666 Comment: This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 211 of the SCN4B protein (p.Thr211Arg). … (more) This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 211 of the SCN4B protein (p.Thr211Arg). This variant is present in population databases (rs201454653, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of SCN4B-related conditions (PMID: 28837624, 30847666). ClinVar contains an entry for this variant (Variation ID: 190895). 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. 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)
Likely benign (Mar 14, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002661401.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 28837624‚ 30821358 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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)
Uncertain significance (Sep 19, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000223642.15 First in ClinVar: May 24, 2015 Last updated: Oct 08, 2024	Comment: Identified in patients with arrhythmia in the published literature (PMID: 28837624, 30821358, 30847666); In silico analysis supports that this missense variant has a deleterious effect … (more) Identified in patients with arrhythmia in the published literature (PMID: 28837624, 30821358, 30847666); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 30821358, 30847666, 28837624, 25741868) (less)
Uncertain significance (Oct 01, 2016)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001148469.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Uncertain significance (Jul 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714994.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Uncertain significance (Jul 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long QT syndrome 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002815185.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959962.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741798.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920745.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021

Comment:

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 211 of the SCN4B protein (p.Thr211Arg). This variant is present in population databases (rs201454653, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of SCN4B-related conditions (PMID: 28837624, 30847666). ClinVar contains an entry for this variant (Variation ID: 190895). 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. 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 alteration is classified as likely 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:

Identified in patients with arrhythmia in the published literature (PMID: 28837624, 30821358, 30847666); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 30821358, 30847666, 28837624, 25741868)

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
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Significant association of rare variant p.Gly8Ser in cardiac sodium channel β4-subunit SCN4B with atrial fibrillation.	Xiong H	Annals of human genetics	2019	PMID: 30821358
Rare variants in genes encoding the cardiac sodium channel and associated compounds and their impact on outcome of catheter ablation of atrial fibrillation.	Husser D	PloS one	2017	PMID: 28837624

Text-mined citations for rs201454653 ...

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_174934.4(SCN4B):c.632C>G (p.Thr211Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201454653 ...