ClinVar Genomic variation as it relates to human health
NM_001288705.3(CSF1R):c.1765G>A (p.Gly589Arg)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001288705.3(CSF1R):c.1765G>A (p.Gly589Arg)
Variation ID: 973001 Accession: VCV000973001.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q32 5: 150061584 (GRCh38) [ NCBI UCSC ] 5: 149441147 (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 Jul 19, 2020 Feb 14, 2024 Sep 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001288705.3:c.1765G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001275634.1:p.Gly589Arg missense NM_001349736.2:c.1765G>A NP_001336665.1:p.Gly589Arg missense NM_001375320.1:c.1765G>A NP_001362249.1:p.Gly589Arg missense NM_001375321.1:c.1321G>A NP_001362250.1:p.Gly441Arg missense NM_005211.4:c.1765G>A NP_005202.2:p.Gly589Arg missense NR_109969.2:n.1892G>A non-coding transcript variant NR_164679.1:n.1821G>A non-coding transcript variant NC_000005.10:g.150061584C>T NC_000005.9:g.149441147C>T NG_012303.2:g.56789G>A - Protein change
- G441R, G589R
- Other names
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- Canonical SPDI
- NC_000005.10:150061583:C:T
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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.
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- Links
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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CSF1R | - | - |
GRCh38 GRCh37 |
759 | 821 |
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
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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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not provided (1) |
no classification provided
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- | RCV001249332.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2023 | RCV001577379.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2023 | RCV003152755.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(Aug 09, 2021)
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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: SCV001804740.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in the heterozygous state in association with hereditary diffuse leukoencephalopathy (Konno et al., 2017; Daida et al., 2017) This variant is associated with the following publications: (PMID: 32276111, 31872055, 28025469, 28824062, 27633805, 28843019, 27680516, 29122458) (less)
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Likely pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy, diffuse hereditary, with spheroids 1
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841698.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.13). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CSF1R related disorder (ClinVar ID: VCV000973001 / PMID: 27680516). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 28824062, 28843019). A different missense change at the same codon (p.Gly589Glu) has been reported to be associated with CSF1R related disorder (ClinVar ID: VCV000038373 / PMID: 22197934). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Limb dystonia (present) , Spasticity (present) , Unsteady gait (present) , Abnormal cerebellum morphology (present) , Leukodystrophy (present) , Hyperreflexia (present)
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Pathogenic
(Sep 27, 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: SCV003439288.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 589 of the CSF1R protein (p.Gly589Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 589 of the CSF1R protein (p.Gly589Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary diffuse leukoencephalopathy with spheroids (PMID: 27680516, 28025469, 28824062, 31872055; external communication). ClinVar contains an entry for this variant (Variation ID: 973001). 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 CSF1R protein function. This variant disrupts the p.Gly589 amino acid residue in CSF1R. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22197934, 30528841). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary diffuse leukoencephalopathy with spheroids
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV001423298.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Likely pathogenic and reported on 09-19-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpretted as Likely pathogenic and reported on 09-19-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Short stature (present) , Abnormality of vision (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Parkinsonism (present) , Abnormality of muscle physiology … (more)
Short stature (present) , Abnormality of vision (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Parkinsonism (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the bladder (present) , Abnormality of leukocytes (present) (less)
Indication for testing: Not Provided
Age: 30-39 years
Sex: female
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2018-09-19
Testing laboratory interpretation: Likely 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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Myelopathy in a patient with leukodystrophy due to CSF1R mutation. | Ho VM | Neurology. Genetics | 2019 | PMID: 31872055 |
Genetic analysis of neurodegenerative diseases in a pathology cohort. | Blauwendraat C | Neurobiology of aging | 2019 | PMID: 30528841 |
Brain calcification in a CSF1R mutation carrier precedes white matter degeneration. | Konno T | Movement disorders : official journal of the Movement Disorder Society | 2017 | PMID: 28843019 |
CSF1R Mutation p.G589R and the Distribution Pattern of Brain Calcification. | Daida K | Internal medicine (Tokyo, Japan) | 2017 | PMID: 28824062 |
MR Spectroscopy in Patients with Hereditary Diffuse Leukoencephalopathy with Spheroids and Asymptomatic Carriers of Colony-stimulating Factor 1 Receptor Mutation. | Abe T | Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine | 2017 | PMID: 28025469 |
Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation. | Konno T | European journal of neurology | 2017 | PMID: 27680516 |
Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. | Rademakers R | Nature genetics | 2011 | PMID: 22197934 |
Text-mined citations for rs1757529135 ...
HelpRecord last updated Mar 30, 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.