NM_031443.4(CCM2):c.55C>T (p.Arg19Ter) AND Cerebral cavernous malformation 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 11, 2023
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:: RCV000644584.10

Allele description [Variation Report for NM_031443.4(CCM2):c.55C>T (p.Arg19Ter)]

NM_031443.4(CCM2):c.55C>T (p.Arg19Ter)

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.55C>T (p.Arg19Ter)

HGVS:

NC_000007.14:g.45038277C>T
NG_016295.1:g.43090C>T
NM_001029835.2:c.118C>T
NM_001167934.2:c.31-25641C>T
NM_001167935.2:c.55C>T
NM_001363458.2:c.55C>T
NM_001363459.2:c.31-25641C>T
NM_031443.4:c.55C>TMANE SELECT
NP_001025006.1:p.Arg40Ter
NP_001161407.1:p.Arg19Ter
NP_001350387.1:p.Arg19Ter
NP_113631.1:p.Arg19Ter
NP_113631.1:p.Arg19Ter
LRG_664t1:c.118C>T
LRG_664t2:c.55C>T
LRG_664:g.43090C>T
LRG_664p1:p.Arg40Ter
LRG_664p2:p.Arg19Ter
NC_000007.13:g.45077876C>T
NM_031443.3:c.55C>T
NR_030770.2:n.137C>T
p.Arg19*

Protein change:

R19*

Links:

NCBI 1000 Genomes Browser:

rs755800734

Molecular consequence:

NM_001167934.2:c.31-25641C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001363459.2:c.31-25641C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_030770.2:n.137C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001029835.2:c.118C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001167935.2:c.55C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001363458.2:c.55C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_031443.4:c.55C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000766284	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18300272, 24689081, 15122722, 23595507, 24466005, 28492532
SCV002806992	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2022)	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

SCV000766284

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 2023)

germline

clinical testing

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

SCV002806992

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 29, 2022)

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

Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex.

Stahl S, Gaetzner S, Voss K, Brackertz B, Schleider E, Sürücü O, Kunze E, Netzer C, Korenke C, Finckh U, Habek M, Poljakovic Z, Elbracht M, Rudnik-Schöneborn S, Bertalanffy H, Sure U, Felbor U.

Hum Mutat. 2008 May;29(5):709-17. doi: 10.1002/humu.20712.

PubMed [citation]

PMID:: 18300272

High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors.

Spiegler S, Najm J, Liu J, Gkalympoudis S, Schröder W, Borck G, Brockmann K, Elbracht M, Fauth C, Ferbert A, Freudenberg L, Grasshoff U, Hellenbroich Y, Henn W, Hoffjan S, Hüning I, Korenke GC, Kroisel PM, Kunstmann E, Mair M, Munk-Schulenburg S, Nikoubashman O, et al.

Mol Genet Genomic Med. 2014 Mar;2(2):176-85. doi: 10.1002/mgg3.60. Epub 2014 Jan 14.

PubMed [citation]

PMID:: 24689081
PMCID:: PMC3960060

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000766284.6

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

Description

This sequence change creates a premature translational stop signal (p.Arg19*) in the CCM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCM2 are known to be pathogenic (PMID: 18300272, 24689081). This variant is present in population databases (rs755800734, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 15122722, 23595507, 24466005). ClinVar contains an entry for this variant (Variation ID: 447028). For these reasons, this variant has been classified as Pathogenic.

#	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, SCV002806992.1

#	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: May 26, 2024

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