VCV000447028.14 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 447028 Accession: VCV000447028.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 45038277 (GRCh38) [ NCBI UCSC ] 7: 45077876 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Feb 14, 2024	Dec 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_031443.4:c.55C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_113631.1:p.Arg19Ter	nonsense
NM_001029835.2:c.118C>T	NP_001025006.1:p.Arg40Ter	nonsense
NM_001167934.2:c.31-25641C>T		intron variant
NM_001167935.2:c.55C>T	NP_001161407.1:p.Arg19Ter	nonsense
NM_001363458.2:c.55C>T	NP_001350387.1:p.Arg19Ter	nonsense
NM_001363459.2:c.31-25641C>T		intron variant
NR_030770.2:n.137C>T		non-coding transcript variant
NC_000007.14:g.45038277C>T
NC_000007.13:g.45077876C>T
NG_016295.1:g.43090C>T
LRG_664:g.43090C>T
LRG_664t1:c.118C>T	LRG_664p1:p.Arg40Ter
LRG_664t2:c.55C>T	LRG_664p2:p.Arg19Ter

... more HGVS ... less HGVS

Protein change

R19*, R40*

Other names

Canonical SPDI

NC_000007.14:45038276:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA4246869 dbSNP: rs755800734 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CCM2		-	-	GRCh38 GRCh37	310	363

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cerebral cavernous malformation 2	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 11, 2023	RCV000644584.11
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 20, 2023	RCV000517288.4
CCM2-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 16, 2023	RCV003389649.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 02, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000612715.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (8) PubMed: 19088124‚ 24466005‚ 19088123‚ 27153162‚ 18300272‚ 23595507‚ 27561926‚ 15122722
Pathogenic (Sep 20, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000748184.4 First in ClinVar: Dec 19, 2017 Last updated: Sep 30, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32170606, 27153162, 24466005, 27561926, 15122722, 19088124, 23595507, 19088123, 18300272, 30701383, 31254430, 27535533, 32615293, 36629374) (less)
Pathogenic (Aug 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CCM2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000852923.2 First in ClinVar: Dec 19, 2017 Last updated: Nov 20, 2023	Comment: The CCM2 c.55C>T variant is predicted to result in premature protein termination (p.Arg19). This variant has been reported to be causative for cerebral cavernous malformations … (more) The CCM2 c.55C>T variant is predicted to result in premature protein termination (p.Arg19). This variant has been reported to be causative for cerebral cavernous malformations (CCMs) in multiple patients (Verlaan et al. 2004. Pub Med ID: 15122722; Stahl et al. 2008. PubMed ID: 18300272; Fusco et al. 2019. PubMed ID: 31254430). At PreventionGenetics, we have detected this variant in several families tested for CCM (Internal Data). Nonsense variants in CCM2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Dec 11, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cerebral cavernous malformation 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000766284.6 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 18300272‚ 24689081‚ 15122722‚ 23595507‚ 24466005 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebral cavernous malformation 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002806992.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32170606, 27153162, 24466005, 27561926, 15122722, 19088124, 23595507, 19088123, 18300272, 30701383, 31254430, 27535533, 32615293, 36629374)

Comment:

The CCM2 c.55C>T variant is predicted to result in premature protein termination (p.Arg19*). This variant has been reported to be causative for cerebral cavernous malformations (CCMs) in multiple patients (Verlaan et al. 2004. Pub Med ID: 15122722; Stahl et al. 2008. PubMed ID: 18300272; Fusco et al. 2019. PubMed ID: 31254430). At PreventionGenetics, we have detected this variant in several families tested for CCM (Internal Data). Nonsense variants in CCM2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Correlation of the venous angioarchitecture of multiple cerebral cavernous malformations with familial or sporadic disease: a susceptibility-weighted imaging study with 7-Tesla MRI.	Dammann P	Journal of neurosurgery	2017	PMID: 27153162
Genetic Screening of Pediatric Cavernous Malformations.	Merello E	Journal of molecular neuroscience : MN	2016	PMID: 27561926
High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors.	Spiegler S	Molecular genetics & genomic medicine	2014	PMID: 24689081
Mutation prevalence of cerebral cavernous malformation genes in Spanish patients.	Mondéjar R	PloS one	2014	PMID: 24466005
CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions.	Riant F	Neurogenetics	2013	PMID: 23595507
A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.	Pagenstecher A	Human molecular genetics	2009	PMID: 19088124
Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.	Akers AL	Human molecular genetics	2009	PMID: 19088123
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	Human mutation	2008	PMID: 18300272
CCM2 mutations account for 13% of cases in a large collection of kindreds with hereditary cavernous malformations.	Verlaan DJ	Annals of neurology	2004	PMID: 15122722

Text-mined citations for rs755800734 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs755800734 ...