NM_201596.3(CACNB2):c.1702G>A (p.Val568Ile) AND Brugada syndrome 4

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 26, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000703877.16

Allele description [Variation Report for NM_201596.3(CACNB2):c.1702G>A (p.Val568Ile)]

NM_201596.3(CACNB2):c.1702G>A (p.Val568Ile)

Gene:

CACNB2:calcium voltage-gated channel auxiliary subunit beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10p12.31

Genomic location:

Preferred name:

NM_201596.3(CACNB2):c.1702G>A (p.Val568Ile)

Other names:

p.V513I:GTA>ATA

HGVS:

NC_000010.11:g.18539443G>A
NG_016195.1:g.403767G>A
NM_000724.4:c.1537G>A
NM_001167945.2:c.1504G>A
NM_001330060.2:c.1423G>A
NM_201570.3:c.1558G>A
NM_201571.4:c.1618G>A
NM_201572.4:c.1546G>A
NM_201590.3:c.1540G>A
NM_201593.3:c.1588G>A
NM_201596.3:c.1702G>AMANE SELECT
NM_201597.3:c.1630G>A
NP_000715.2:p.Val513Ile
NP_001161417.1:p.Val502Ile
NP_001316989.1:p.Val475Ile
NP_963864.1:p.Val520Ile
NP_963865.2:p.Val540Ile
NP_963866.2:p.Val516Ile
NP_963884.2:p.Val514Ile
NP_963887.2:p.Val530Ile
NP_963890.2:p.Val568Ile
NP_963891.1:p.Val544Ile
LRG_381t1:c.1702G>A
LRG_381t2:c.1540G>A
LRG_381:g.403767G>A
LRG_381p1:p.Val568Ile
LRG_381p2:p.Val514Ile
NC_000010.10:g.18828372G>A
NM_000724.3:c.1537G>A
NM_201590.2:c.1540G>A

Protein change:

V475I

Links:

dbSNP: rs142639223

NCBI 1000 Genomes Browser:

rs142639223

Molecular consequence:

NM_000724.4:c.1537G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167945.2:c.1504G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330060.2:c.1423G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201570.3:c.1558G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201571.4:c.1618G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201572.4:c.1546G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201590.3:c.1540G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201593.3:c.1588G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201596.3:c.1702G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201597.3:c.1630G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Brugada syndrome 4 (BRGDA4)
Identifiers:: MONDO: MONDO:0012743; MedGen: C2678477; Orphanet: 130; OMIM: 611876

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000832801	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25650408, 28492532
SCV002050116	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Jan 4, 2021)	germline	clinical testing	Citation Link,
SCV002512721	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000832801

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002050116

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Uncertain significance
(Jan 4, 2021)

germline

clinical testing

Citation Link,

SCV002512721

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 15, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome.

Le Scouarnec S, Karakachoff M, Gourraud JB, Lindenbaum P, Bonnaud S, Portero V, Duboscq-Bidot L, Daumy X, Simonet F, Teusan R, Baron E, Violleau J, Persyn E, Bellanger L, Barc J, Chatel S, Martins R, Mabo P, Sacher F, Haïssaguerre M, Kyndt F, Schmitt S, et al.

Hum Mol Genet. 2015 May 15;24(10):2757-63. doi: 10.1093/hmg/ddv036. Epub 2015 Feb 3.

PubMed [citation]

PMID:: 25650408

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000832801.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 514 of the CACNB2 protein (p.Val514Ile). This variant is present in population databases (rs142639223, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Brugada syndrome (PMID: 25650408). ClinVar contains an entry for this variant (Variation ID: 190717). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNB2 protein function with a negative predictive value of 80%. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002050116.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CACNB2 c.1540G>A; p.Val514Ile variant (rs142639223), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 190717). This variant is found in the general population with an overall allele frequency of 0.02% (62/282604 alleles) in the Genome Aggregation Database. The valine at codon 514 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.16). Due to limited information, the clinical significance of the p.Val514Ile variant is uncertain at this time. Gene statement: Although variants in CACNB2 have been associated with Brugada syndrome 4 (MIM: 611876), the evidence supporting this association is limited (Hosseini 2018). Hosseini et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome Circulation, 2018 Sep 18;138(12):1195-1205.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: BP4 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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