NM_031443.4(CCM2):c.1A>G (p.Met1Val) AND Cerebral cavernous malformation 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 17, 2022
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:: RCV000002803.10

Allele description [Variation Report for NM_031443.4(CCM2):c.1A>G (p.Met1Val)]

NM_031443.4(CCM2):c.1A>G (p.Met1Val)

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.1A>G (p.Met1Val)

HGVS:

NC_000007.14:g.45000334A>G
NG_016295.1:g.5147A>G
NM_001167934.2:c.1A>G
NM_001167935.2:c.1A>G
NM_001363458.2:c.1A>G
NM_001363459.2:c.1A>G
NM_031443.4:c.1A>GMANE SELECT
NP_001161406.1:p.Met1Val
NP_001161407.1:p.Met1Val
NP_001350387.1:p.Met1Val
NP_001350388.1:p.Met1Val
NP_113631.1:p.Met1Val
NP_113631.1:p.Met1Val
LRG_664t2:c.1A>G
LRG_664:g.5147A>G
LRG_664p2:p.Met1Val
NC_000007.13:g.45039933A>G
NM_031443.3:c.1A>G

Protein change:

M1V; MET1VAL

Links:

OMIM: 607929.0005; dbSNP: rs137852842

NCBI 1000 Genomes Browser:

rs137852842

Molecular consequence:

NM_001167934.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001167935.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001363458.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001363459.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_031443.4:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001167934.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167935.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363458.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363459.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_031443.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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cyclin F [Homo sapiens]
cyclin F [Homo sapiens]
gi|4502621|ref|NP_001752.1|

Protein
fertilin alpha protein [Pongo pygmaeus]
fertilin alpha protein [Pongo pygmaeus]
gi|2632092|emb|CAA75659.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022961	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2004)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002180484	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14740320, 27792856, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000022961

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2004)

germline

literature only

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

SCV002180484

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2022)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations within the MGC4607 gene cause cerebral cavernous malformations.

Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, et al.

Am J Hum Genet. 2004 Feb;74(2):326-37. Epub 2004 Jan 22.

PubMed [citation]

PMID:: 14740320
PMCID:: PMC1181930

Review of familial cerebral cavernous malformations and report of seven additional families.

de Vos IJ, Vreeburg M, Koek GH, van Steensel MA.

Am J Med Genet A. 2017 Feb;173(2):338-351. doi: 10.1002/ajmg.a.38028. Epub 2016 Oct 28. Review.

PubMed [citation]

PMID:: 27792856

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000022961.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of a family (family C038) with cerebral cavernous malformations (CCM2; 603284), Denier et al. (2004) found a heterozygous mutation in the initiating ATG codon of the CCM2 gene, changing nucleotide 1 from A to G (c.1A-G, NM_031443). In this family, 2 sisters and the daughter of 1 of them were affected.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002180484.4

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

Description

Disruption of the initiator codon has been observed in individual(s) with cerebral cavernous malformations (PMID: 14740320; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2684). This variant disrupts a region of the CCM2 protein in which other variant(s) (p.Leu212Pro) have been determined to be pathogenic (PMID: 27792856; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the CCM2 mRNA. The next in-frame methionine is located at codon 303. This variant is not present in population databases (gnomAD no frequency).

#	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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