ClinVar Genomic variation as it relates to human health
NM_000435.3(NOTCH3):c.3664T>G (p.Cys1222Gly)
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.
Likely pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000435.3(NOTCH3):c.3664T>G (p.Cys1222Gly)
Variation ID: 425164 Accession: VCV000425164.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.12 19: 15179079 (GRCh38) [ NCBI UCSC ] 19: 15289890 (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 May 8, 2017 Apr 15, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000435.3:c.3664T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000426.2:p.Cys1222Gly missense NC_000019.10:g.15179079A>C NC_000019.9:g.15289890A>C NG_009819.1:g.26903T>G - Protein change
- C1222G
- Other names
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- Canonical SPDI
- NC_000019.10:15179078:A:C
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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.
Exome Aggregation Consortium (ExAC) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00010
The Genome Aggregation Database (gnomAD) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
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 | ||
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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
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. |
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NOTCH3 | - | - |
GRCh38 GRCh37 |
1486 | 1524 |
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
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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 (3) |
criteria provided, conflicting classifications
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Dec 13, 2023 | RCV000487935.26 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 10, 2017 | RCV000499633.7 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 1, 2019 | RCV000999639.4 |
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
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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
(May 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000596041.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440794.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Uncertain significance
(Aug 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001879606.3
First in ClinVar: Sep 19, 2021 Last updated: Jan 26, 2024 |
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features consistent with CADASIL. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673). This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. (less)
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Uncertain significance
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002255020.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1222 of the NOTCH3 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1222 of the NOTCH3 protein (p.Cys1222Gly). This variant is present in population databases (rs199638166, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with NOTCH3-related conditions or cognitively healthy elderly controls (PMID: 24840674, 26305465, 32573853, 32732295). ClinVar contains an entry for this variant (Variation ID: 425164). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. 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)
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Likely pathogenic
(Nov 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000575149.26
First in ClinVar: May 08, 2017 Last updated: Apr 15, 2024 |
Comment:
NOTCH3: PM1:Strong, PS4:Moderate
Number of individuals with the variant: 4
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not provided
(-)
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no classification provided
Method: phenotyping only
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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - CureCADASIL
Accession: SCV001156359.1
First in ClinVar: Feb 07, 2020 Last updated: Feb 07, 2020 |
Comment:
Variant interpreted as Pathogenic and reported on 11-07-2016 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 11-07-2016 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of eye movement (present) , Abnormality of globe size (present) , Hypermetropia (present) , Abnormality iris morphology (present) , Abnormality of the lens (present) … (more)
Abnormality of eye movement (present) , Abnormality of globe size (present) , Hypermetropia (present) , Abnormality iris morphology (present) , Abnormality of the lens (present) , Myopia (present) , Ptosis (present) , Abnormal retinal morphology (present) , Vertigo (present) , Aplasia/Hypoplasia of the ear (present) , Hyperacusis (present) , Mixed hearing impairment (present) , Tinnitus (present) , Sensorineural hearing loss (present) , Abnormality of the chin (present) , Oral cleft (present) , Abnormal facial shape (present) , Abnormality of the oral cavity (present) , Abnormality of the mouth (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Dilatation (present) , Syncope (present) , Abnormality of cardiovascular system morphology (present) , Hypercholesterolemia (present) , Stroke (present) , Abnormality of the anus (present) , Feeding difficulties (present) , Abnormality of the intestine (present) , Abnormality of the liver (present) , Abnormality of the pancreas (present) , Abnormality of the large intestine (present) , Abnormality of the stomach (present) , Abnormality of the bladder (present) , Abnormality of the female genitalia (present) , Abnormality of reproductive system physiology (present) , Abnormal renal physiology (present) , Abnormal renal morphology (present) , Abnormality of the male genitalia (present) , Abnormality of the urethra (present) , Abnormality of the ureter (present) , Abnormality of urine homeostasis (present) , Adrenal hyperplasia (present) , Delayed puberty (present) , Diabetes insipidus (present) , Precocious puberty (present) , Goiter (present) , Growth hormone deficiency (present) , Hyperthyroidism (present) , Hypogonadism (present) , Abnormality of the parathyroid physiology (present) , Diabetes mellitus type 2 (present) , Anxiety (present) , Depressivity (present) (less)
Age: 60-69 years
Sex: female
Testing laboratory: Athena Diagnostics Inc
Date variant was reported to submitter: 2016-11-07
Testing laboratory interpretation: Pathogenic
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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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Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia. | Juhosová M | Neurogenetics | 2023 | PMID: 36401683 |
Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance. | Rutten JW | Neurology | 2020 | PMID: 32732295 |
Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities. | Ramirez J | Movement disorders : official journal of the Movement Disorder Society | 2020 | PMID: 32573853 |
Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. | Rutten JW | Annals of clinical and translational neurology | 2016 | PMID: 27844030 |
Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke. | Kilarski LL | PloS one | 2015 | PMID: 26305465 |
Changing clinical patterns and increasing prevalence in CADASIL. | Moreton FC | Acta neurologica Scandinavica | 2014 | PMID: 24840674 |
Text-mined citations for rs199638166 ...
HelpRecord last updated Apr 15, 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.