NM_201596.3(CACNB2):c.1735G>A (p.Val579Met) AND Brugada syndrome 4

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 24, 2022
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:: RCV001046971.8

Allele description [Variation Report for NM_201596.3(CACNB2):c.1735G>A (p.Val579Met)]

NM_201596.3(CACNB2):c.1735G>A (p.Val579Met)

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.1735G>A (p.Val579Met)

HGVS:

NC_000010.11:g.18539476G>A
NG_016195.1:g.403800G>A
NM_000724.4:c.1570G>A
NM_001167945.2:c.1537G>A
NM_001330060.2:c.1456G>A
NM_201570.3:c.1591G>A
NM_201571.4:c.1651G>A
NM_201572.4:c.1579G>A
NM_201590.3:c.1573G>A
NM_201593.3:c.1621G>A
NM_201596.3:c.1735G>AMANE SELECT
NM_201597.3:c.1663G>A
NP_000715.2:p.Val524Met
NP_001161417.1:p.Val513Met
NP_001316989.1:p.Val486Met
NP_963864.1:p.Val531Met
NP_963865.2:p.Val551Met
NP_963866.2:p.Val527Met
NP_963884.2:p.Val525Met
NP_963887.2:p.Val541Met
NP_963890.2:p.Val579Met
NP_963891.1:p.Val555Met
LRG_381t1:c.1735G>A
LRG_381t2:c.1573G>A
LRG_381:g.403800G>A
LRG_381p1:p.Val579Met
LRG_381p2:p.Val525Met
NC_000010.10:g.18828405G>A
NC_000010.10:g.18828405G>A
NM_201590.2:c.1573G>A
NM_201596.2:c.1735G>A

Protein change:

V486M

Links:

dbSNP: rs544535665

NCBI 1000 Genomes Browser:

rs544535665

Molecular consequence:

NM_000724.4:c.1570G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167945.2:c.1537G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330060.2:c.1456G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201570.3:c.1591G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201571.4:c.1651G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201572.4:c.1579G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201590.3:c.1573G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201593.3:c.1621G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201596.3:c.1735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201597.3:c.1663G>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
SCV001210898	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 24, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28341588, 30847666, 28492532
SCV002783274	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 9, 2021)	unknown	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

SCV001210898

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 24, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002783274

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 9, 2021)

unknown

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease.

Proost D, Saenen J, Vandeweyer G, Rotthier A, Alaerts M, Van Craenenbroeck EM, Van Crombruggen J, Mortier G, Wuyts W, Vrints C, Del Favero J, Loeys B, Van Laer L.

J Mol Diagn. 2017 May;19(3):445-459. doi: 10.1016/j.jmoldx.2017.01.010. Epub 2017 Mar 22.

PubMed [citation]

PMID:: 28341588

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

van Lint FHM, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH, Christiaans I.

Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.

PubMed [citation]

PMID:: 30847666
PMCID:: PMC6533346

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001210898.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 666376). This variant is also known as c.1735G>A p.V579M. This missense change has been observed in individual(s) with Brugada syndrome (PMID: 28341588, 30847666). This variant is present in population databases (rs544535665, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 525 of the CACNB2 protein (p.Val525Met).

#	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 Fulgent Genetics, Fulgent Genetics, SCV002783274.1

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

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

Last Updated: Oct 20, 2024

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