VCV000001653.7 - ClinVar

NM_014043.4(CHMP2B):c.442G>T (p.Asp148Tyr)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Uncertain significance

1 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014043.4(CHMP2B):c.442G>T (p.Asp148Tyr)

Variation ID: 1653 Accession: VCV000001653.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p11.2 3: 87253421 (GRCh38) [ NCBI UCSC ] 3: 87302571 (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	Apr 4, 2013	Mar 4, 2025	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014043.4:c.442G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_054762.2:p.Asp148Tyr	missense
NM_001244644.2:c.319G>T	NP_001231573.1:p.Asp107Tyr	missense
NC_000003.12:g.87253421G>T
NC_000003.11:g.87302571G>T
NG_007885.1:g.31159G>T
	Q9UQN3:p.Asp148Tyr

... more HGVS ... less HGVS

Protein change

D148Y, D107Y

Other names

Canonical SPDI

NC_000003.12:87253420:G:T

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

Links

ClinGen: CA224974 UniProtKB: Q9UQN3#VAR_023383 OMIM: 609512.0002 dbSNP: rs63750653 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.
CHMP2B		-	-	GRCh38 GRCh37	184	218

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.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 7	Uncertain significance (3)	criteria provided, single submitter	Jan 22, 2024	RCV000001720.8
not provided	not provided (1)	no classification provided	-	RCV000084275.2

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.	Expand all rows Collapse all rows 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.
Uncertain significance (Jan 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004569777.2 First in ClinVar: Feb 28, 2024 Last updated: Mar 04, 2025	Publications: PubMed (2) PubMed: 16041373‚ 17956895 Comment: show This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 148 of the CHMP2B protein (p.Asp148Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with frontotemporal dementia (PMID: 16041373). ClinVar contains an entry for this variant (Variation ID: 1653). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHMP2B function (PMID: 17956895). 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 01, 2005) N Not contributing to aggregate classification	no assertion criteria provided	FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 7	OMIM Accession: SCV000021876.3 First in ClinVar: Apr 04, 2013 Last updated: Jan 09, 2021	Publications: PubMed (1) PubMed: 16041373 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a patient with frontotemporal dementia (FTDALS7; 600795), Skibinski et al. (2005) identified a 442G-T transversion in exon 5 of the CHMP2B gene, resulting in … (more) In a patient with frontotemporal dementia (FTDALS7; 600795), Skibinski et al. (2005) identified a 442G-T transversion in exon 5 of the CHMP2B gene, resulting in an asp148-to-tyr (D148Y) substitution in the conserved Snf-7 domain. The patient was 1 of 400 unrelated European patients studied. (less)

not provided (-) N Not contributing to aggregate classification	no classification provided	not provided	VIB Department of Molecular Genetics, University of Antwerp Accession: SCV000116411.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_379	Observation: 1 Collection method: not provided Allele origin: unknown Affected status: not provided Observation 1 Collection method: not provided Allele origin: unknown Affected status: not provided

not provided (-) N Not contributing to aggregate classification	no classification provided	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7	GeneReviews Accession: SCV000041244.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 16041373‚ 20301378 BookShelf: NBK1199 BookShelf: NBK1199 Observation: 1 Collection method: literature only Allele origin: unknown Affected status: not provided Observation 1 Collection method: literature only Allele origin: unknown Affected status: not provided

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 148 of the CHMP2B protein (p.Asp148Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with frontotemporal dementia (PMID: 16041373). ClinVar contains an entry for this variant (Variation ID: 1653). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHMP2B function (PMID: 17956895). 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CHMP2B Frontotemporal Dementia.	Adam MP	-	2020	PMID: 20301378
CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro.	van der Zee J	Human molecular genetics	2008	PMID: 17956895
Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.	Skibinski G	Nature genetics	2005	PMID: 16041373

Text-mined citations for rs63750653 ...

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 May 17, 2025