VCV000161212.42 - ClinVar

NM_201596.3(CACNB2):c.1511C>T (p.Thr504Ile)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(2); Likely benign(7)

10 out of 15 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_201596.3(CACNB2):c.1511C>T (p.Thr504Ile)

Variation ID: 161212 Accession: VCV000161212.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10p12.31 10: 18539252 (GRCh38) [ NCBI UCSC ] 10: 18828181 (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	Dec 7, 2014	Apr 20, 2025	Feb 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_201596.3:c.1511C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_963890.2:p.Thr504Ile	missense
NM_201590.3:c.1349C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_963884.2:p.Thr450Ile	missense
NM_000724.4:c.1346C>T	NP_000715.2:p.Thr449Ile	missense
NM_001167945.2:c.1313C>T	NP_001161417.1:p.Thr438Ile	missense
NM_001330060.2:c.1232C>T	NP_001316989.1:p.Thr411Ile	missense
NM_201570.3:c.1367C>T	NP_963864.1:p.Thr456Ile	missense
NM_201571.4:c.1427C>T	NP_963865.2:p.Thr476Ile	missense
NM_201572.4:c.1355C>T	NP_963866.2:p.Thr452Ile	missense
NM_201593.3:c.1397C>T	NP_963887.2:p.Thr466Ile	missense
NM_201597.3:c.1439C>T	NP_963891.1:p.Thr480Ile	missense
NC_000010.11:g.18539252C>T
NC_000010.10:g.18828181C>T
NG_016195.1:g.403576C>T
LRG_381:g.403576C>T
LRG_381t1:c.1511C>T	LRG_381p1:p.Thr504Ile
LRG_381t2:c.1349C>T	LRG_381p2:p.Thr450Ile

... more HGVS ... less HGVS

Protein change

T449I, T450I, T504I, T411I, T452I, T466I, T480I, T456I, T476I, T438I

Other names

p.T449I:ACT>ATT

Canonical SPDI

NC_000010.11:18539251: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.

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00146

The Genome Aggregation Database (gnomAD), exomes 0.00148

Exome Aggregation Consortium (ExAC) 0.00158

Trans-Omics for Precision Medicine (TOPMed) 0.00168

The Genome Aggregation Database (gnomAD) 0.00181

Links

ClinGen: CA235677 dbSNP: rs143326262 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.
CACNB2		-	-	GRCh38 GRCh37	1025	1054

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)	no assertion criteria provided	Jun 1, 2014	RCV000148450.3
not provided	Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2025	RCV000170869.22
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Feb 11, 2019	RCV000251462.5
not specified	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Dec 18, 2017	RCV000185500.16
Brugada syndrome 4	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2025	RCV000231277.15
Ventricular tachycardia	Likely benign (1)	criteria provided, single submitter	Jan 31, 2019	RCV000852601.1
CACNB2-related disorder	Likely benign (1)	no assertion criteria provided	May 2, 2024	RCV004745215.1
Long QT syndrome	Benign (1)	criteria provided, single submitter	Jan 8, 2024	RCV003318352.3

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.
Likely benign (Jun 24, 2013) C Contributing to aggregate classification	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Not provided Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000050763.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 3
Uncertain significance (Mar 29, 2016) C Contributing to aggregate classification	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: SCV000538564.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	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: Only 1 proband in HGMD, ExAC: 0.2% (159/66588) European chromosomes (less) Method: Genome/Exome Filtration
Likely benign (Jun 02, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Brugada syndrome 4 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743842.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (Dec 18, 2017) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917105.1 First in ClinVar: May 31, 2019 Last updated: May 31, 2019	Publications: PubMed (5) PubMed: 26230511‚ 20817017‚ 27711072‚ 23414114‚ 26636822 Comment: Variant summary: The CACNB2 c.1349C>T (p.Thr450Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant … (more) Variant summary: The CACNB2 c.1349C>T (p.Thr450Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 449/289284 control chromosomes (1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00279 (353/126520). This frequency is about 893 times the estimated maximal expected allele frequency of a pathogenic CACNB2 variant (0.0000031), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Though this variant has been reported in 2 individuals in a single family with BrS in an early study (Burashnikov 2010), later population studies indicated that the variant is not associated with BrS specific ECG patterns (Risgaard 2013, Ghouse 2017) and one study reports non-segregation of the variant with disease in a family (Allegue_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign. (less)
Likely benign (Oct 17, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000223424.8 First in ClinVar: May 23, 2015 Last updated: Nov 25, 2023	Comment: See Variant Classification Assertion Criteria.
Likely benign (Feb 11, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000319990.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 20817017‚ 23414114‚ 23861362‚ 24055113‚ 25637381 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)
Likely benign (Feb 01, 2025) C Contributing to aggregate classification	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: SCV004126524.13 First in ClinVar: Nov 20, 2023 Last updated: Apr 20, 2025	Comment: CACNB2: BP4, BS2; ENSG00000240291: BS2 Number of individuals with the variant: 3
Likely benign (Jan 31, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ventricular tachycardia Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995304.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Likely benign (Jan 31, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Brugada syndrome 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291906.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 25, 2025
Benign (Jan 08, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Dept of Medical Biology Variant Classification) Method: research	Long QT syndrome Affected status: yes Allele origin: paternal	Dept of Medical Biology, Uskudar University Accession: SCV004021967.3 First in ClinVar: Jul 29, 2023 Last updated: Apr 13, 2025	Comment: Criteria: BS1, BS2 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Turkish Geographic origin: Turkey
Uncertain significance (Jun 01, 2014) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Brugada syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190149.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not specified 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: SCV001925178.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not specified 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: SCV001955766.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (May 02, 2024) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	CACNB2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005351766.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
not provided (-) N Not contributing to aggregate classification	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV003761505.2 First in ClinVar: Feb 07, 2023 Last updated: Apr 13, 2025	Comment: Variant classified as Uncertain significance and reported on 11-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more) Variant classified as Uncertain significance and reported on 11-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Conductive hearing impairment (present) , Sensorineural hearing loss disorder (present) , Mixed hearing impairment (present) , Hearing impairment (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Abnormality of the nervous system (present) , Abnormality of coordination (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Hyperpigmentation of the skin (present) , Cardiac arrhythmia (present) , Hypertensive disorder (present) Age: 30-39 years Sex: female Method: Gene Panel Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2015-11-08 Testing laboratory interpretation: Uncertain significance
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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: Only 1 proband in HGMD, ExAC: 0.2% (159/66588) European chromosomes

Comment:

Variant summary: The CACNB2 c.1349C>T (p.Thr450Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 449/289284 control chromosomes (1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00279 (353/126520). This frequency is about 893 times the estimated maximal expected allele frequency of a pathogenic CACNB2 variant (0.0000031), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Though this variant has been reported in 2 individuals in a single family with BrS in an early study (Burashnikov 2010), later population studies indicated that the variant is not associated with BrS specific ECG patterns (Risgaard 2013, Ghouse 2017) and one study reports non-segregation of the variant with disease in a family (Allegue_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign.

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:

Variant classified as Uncertain significance and reported on 11-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality.	Ghouse J	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27711072
Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel.	Celestino-Soper PB	PloS one	2015	PMID: 26636822
Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome.	Allegue C	PloS one	2015	PMID: 26230511
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Actionable, pathogenic incidental findings in 1,000 participants' exomes.	Dorschner MO	American journal of human genetics	2013	PMID: 24055113
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362
High prevalence of genetic variants previously associated with Brugada syndrome in new exome data.	Risgaard B	Clinical genetics	2013	PMID: 23414114
Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.	Burashnikov E	Heart rhythm	2010	PMID: 20817017

Text-mined citations for rs143326262 ...

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 Apr 20, 2025

ClinVar Genomic variation as it relates to human health

NM_201596.3(CACNB2):c.1511C>T (p.Thr504Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143326262 ...