ClinVar Genomic variation as it relates to human health
NM_024408.4(NOTCH2):c.7198C>T (p.Arg2400Ter)
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.
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(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024408.4(NOTCH2):c.7198C>T (p.Arg2400Ter)
Variation ID: 518450 Accession: VCV000518450.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p12 1: 119915524 (GRCh38) [ NCBI UCSC ] 1: 120458147 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 13, 2018 Feb 14, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024408.4:c.7198C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077719.2:p.Arg2400Ter nonsense NC_000001.11:g.119915524G>A NC_000001.10:g.120458147G>A NG_008163.1:g.159130C>T - Protein change
- R2400*
- Other names
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- Canonical SPDI
- NC_000001.11:119915523:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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NOTCH2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1473 | 1498 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Nov 24, 2023 | RCV000617014.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 30, 2022 | RCV002508237.1 |
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
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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
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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
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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. |
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Uncertain significance
(Mar 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hajdu-Cheney syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002505592.1
First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022 |
Comment:
_x000D_ Criteria applied: PVS1_MOD
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hajdu-Cheney syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521744.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported to be associated with NOTCH2 related disorder (ClinVar ID: VCV000518450 / PMID: 21378985). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Developmental cataract (present) , Iris coloboma (present) , Clubfoot (present) , Microcephaly (present) , Orofacial cleft (present)
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Pathogenic
(Dec 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002818083.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 72 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 72 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 24296945, 21378985, 25141821, 24995648, 29453417, 29698804, 32978145, 31785789, 29618366, 24077912, 23389697, 28832562, 21793104, 33448881, 25590979) (less)
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Pathogenic
(Feb 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hajdu-Cheney syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041181.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Nov 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hajdu-Cheney syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004291983.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg2400*) in the NOTCH2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg2400*) in the NOTCH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acid(s) of the NOTCH2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Hajdu-Cheney syndrome (PMID: 21378985, 29698804). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 518450). This protein change is located in a region of the NOTCH2 protein where a significant number of previously reported NOTCH2 nonsense and frameshift mutations are found (PMID: 21378985, 23389697, 26627824). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2017)
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no assertion criteria provided
Method: clinical testing
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Hajdu-Cheney syndrome
Hajdu-Cheney syndrome in a male
(more...)
Affected status: yes
Allele origin:
de novo
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Metabolic Disease laboratory, Sheba Medical Center
Accession: SCV000734848.1
First in ClinVar: Apr 13, 2018 Last updated: Apr 13, 2018 |
Number of individuals with the variant: 1
Family history: no
Ethnicity/Population group: Ashkenazi Jewish
Geographic origin: Israel
Tissue: Blood
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotype variability in Hajdu-Cheney syndrome. | Regev M | European journal of medical genetics | 2019 | PMID: 29698804 |
Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption. | Canalis E | The Journal of biological chemistry | 2016 | PMID: 26627824 |
Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome. | Zhao W | Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA | 2013 | PMID: 23389697 |
Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. | Simpson MA | Nature genetics | 2011 | PMID: 21378985 |
Text-mined citations for rs1325403451 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.