NM_031443.4(CCM2):c.30+1G>A AND Cerebral cavernous malformation 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 19, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000791931.9

Allele description [Variation Report for NM_031443.4(CCM2):c.30+1G>A]

NM_031443.4(CCM2):c.30+1G>A

Genes:

LOC129998395:ATAC-STARR-seq lymphoblastoid silent region 18162 [Gene]
CCM2:CCM2 scaffold protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_031443.4(CCM2):c.30+1G>A

HGVS:

NC_000007.14:g.45000364G>A
NG_016295.1:g.5177G>A
NG_177841.1:g.317G>A
NM_001167934.2:c.30+1G>A
NM_001167935.2:c.30+1G>A
NM_001363458.2:c.30+1G>A
NM_001363459.2:c.30+1G>A
NM_031443.4:c.30+1G>AMANE SELECT
LRG_664t2:c.30+1G>A
LRG_664:g.5177G>A
NC_000007.13:g.45039963G>A
NM_031443.3:c.30+1G>A

Links:

dbSNP: rs1562848479

NCBI 1000 Genomes Browser:

rs1562848479

Molecular consequence:

NM_001167934.2:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001167935.2:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001363458.2:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001363459.2:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_031443.4:c.30+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Cerebral cavernous malformation 2
Synonyms:: Cerebral cavernous malformations 2
Identifiers:: MONDO: MONDO:0011304; MedGen: C1864041; Orphanet: 221061; OMIM: 603284

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000931201	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 19, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15122722, 19088124, 16199547, 18300272, 24689081, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000931201

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 19, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Citations

PubMed

CCM2 mutations account for 13% of cases in a large collection of kindreds with hereditary cavernous malformations.

Verlaan DJ, Laurent SB, Rochefort DL, Liquori CL, Marchuk DA, Siegel AM, Rouleau GA.

Ann Neurol. 2004 May;55(5):757-8. No abstract available.

PubMed [citation]

PMID:: 15122722

A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.

Pagenstecher A, Stahl S, Sure U, Felbor U.

Hum Mol Genet. 2009 Mar 1;18(5):911-8. doi: 10.1093/hmg/ddn420. Epub 2008 Dec 16.

PubMed [citation]

PMID:: 19088124
PMCID:: PMC2640205

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000931201.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that disruption of this splice site affects CCM2 function (PMID: 19088124). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 590655). This variant is also known as IVS+1G>A. Disruption of this splice site has been observed in individual(s) with cerebral cavernous malformations (PMID: 15122722, 19088124). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the CCM2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CCM2 are known to be pathogenic (PMID: 18300272, 24689081).

#	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

Last Updated: Sep 29, 2024

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