ClinVar Genomic variation as it relates to human health
NM_017613.4(DONSON):c.82A>C (p.Ser28Arg)
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(1); Uncertain significance(3); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017613.4(DONSON):c.82A>C (p.Ser28Arg)
Variation ID: 431446 Accession: VCV000431446.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 33588560 (GRCh38) [ NCBI UCSC ] 21: 34960866 (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 15, 2018 Apr 15, 2024 Oct 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017613.4:c.82A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060083.1:p.Ser28Arg missense NC_000021.9:g.33588560T>G NC_000021.8:g.34960866T>G - Protein change
- S28R
- Other names
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- Canonical SPDI
- NC_000021.9:33588559:T:G
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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) 0.00000
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD) 0.00090
Trans-Omics for Precision Medicine (TOPMed) 0.00146
The Genome Aggregation Database (gnomAD), exomes 0.00171
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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DONSON | - | - |
GRCh38 GRCh37 |
216 | 283 |
Conditions - Germline
Condition
Help
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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Pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2021 | RCV000623846.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 5, 2018 | RCV000626267.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 13, 2022 | RCV001856993.13 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 31, 2022 | RCV002470886.3 |
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 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-micromelia syndrome
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746920.3
First in ClinVar: Apr 29, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 2
Age: 30-39 years
Sex: female
Geographic origin: Iran
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Likely benign
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, short stature, and limb abnormalities
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766782.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly, short stature, and limb abnormalities (MIM#617604) and microcephaly-micromelia syndrome (MIM#251230). (I) 0106 - This gene is associated with autosomal recessive disease. However there has been one previous report of an individual with femoral facial syndrome who was only heterozygous for one DONSON variant (PMID: 31407851). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (141 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. This variant has been observed on an ancetral haplotype and in cis with another missense variant p.(Lys489Thr) that is considered pathogenic in at least seven unrelated individuals (ClinVar, PMID: 28191891). This variant has also been classified as pathogenic and as a VUS by clinical laboratories in ClinVar. (SB) 1004 - This variant has moderate functional evidence supporting normal protein function. Western blot and immunoblot studies have shown this variant does not reduce the levels of DONSON protein (PMID: 28191891). This variant has also been shown to rescue spontaneous replication fork stalling observed on DONSON depletion (PMID: 28191891). (SB) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Oct 13, 2022)
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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: SCV002306206.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the DONSON protein (p.Ser28Arg). … (more)
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the DONSON protein (p.Ser28Arg). This variant is present in population databases (rs768071555, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with microcephalic dwarfism (PMID: 28191891). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 431446). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DONSON 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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Pathogenic
(Sep 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742269.4
First in ClinVar: Apr 15, 2018 Last updated: Feb 07, 2023 |
Comment:
The c.82A>C (p.S28R) alteration is located in exon 1 (coding exon 1) of the DONSON gene. This alteration results from an A to C substitution … (more)
The c.82A>C (p.S28R) alteration is located in exon 1 (coding exon 1) of the DONSON gene. This alteration results from an A to C substitution at nucleotide position 82, causing the serine (S) at amino acid position 28 to be replaced by an arginine (R). The c.1466A>C (p.K489T) alteration is located in exon 9 (coding exon 9) of the DONSON gene. This alteration results from an A to C substitution at nucleotide position 1466, causing the lysine (K) at amino acid position 489 to be replaced by a threonine (T). The p.S28R and p.K489T alterations have been observed to be linked in cis and form a haplotype which also includes an intronic c.786-33A>G change (Reynolds, 2017). Based on the available evidence, the DONSON c.[82A>C;1466A>C] (p.[S28R;K489T]) haplotype is classified as pathogenic. VUS if seen without c.1466A>C Based on data from gnomAD, the C allele has an overall frequency of 0.08% (25/33238) total alleles studied. The highest observed frequency was 0.66% (3/452) of Ashkenazi Jewish alleles. This haplotype including p.S28R, p.K489T, and c.786-33A>G was detected in the heterozygous state in trans with truncating variants in five unrelated patients with microcephalic dwarfism (Reynolds, 2017). The p.S28R and p.K489T variants were both identified in the homozygous state in an individual from a consanguineous family with spondylo-epi-metaphyseal dysplasia (SEMD) who had many additional homozygous variants in other genes as well (Guo, 2017). The p.S28 and p.K489 amino acids are not well conserved in available vertebrate species. Of the three variants in the common haplotype, only p.K489T was found to have a negative effect in functional studies. The p.S28R alteration failed to reduce protein levels and was able to complement loss of endogenous DONSON during replication fork stalling (Reynolds, 2017). The p.S28R and p.K489T alterations are predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544667.10
First in ClinVar: Jul 09, 2022 Last updated: Apr 15, 2024 |
Comment:
DONSON: PM2:Supporting, BS3:Supporting
Number of individuals with the variant: 1
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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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Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities. | Karaca E | American journal of medical genetics. Part A | 2019 | PMID: 31407851 |
Identification of biallelic EXTL3 mutations in a novel type of spondylo-epi-metaphyseal dysplasia. | Guo L | Journal of human genetics | 2017 | PMID: 28331220 |
Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. | Reynolds JJ | Nature genetics | 2017 | PMID: 28191891 |
Text-mined citations for rs768071555 ...
HelpRecord last updated Apr 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.