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NM_017613.4(DONSON):c.82A>C (p.Ser28Arg) AND Microcephaly, short stature, and limb abnormalities

Germline classification:
Likely benign (1 submission)
Last evaluated:
Mar 31, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002470886.3

Allele description [Variation Report for NM_017613.4(DONSON):c.82A>C (p.Ser28Arg)]

NM_017613.4(DONSON):c.82A>C (p.Ser28Arg)

Gene:
DONSON:DNA replication fork stabilization factor DONSON [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.11
Genomic location:
Preferred name:
NM_017613.4(DONSON):c.82A>C (p.Ser28Arg)
HGVS:
  • NC_000021.9:g.33588560T>G
  • NM_017613.4:c.82A>CMANE SELECT
  • NP_060083.1:p.Ser28Arg
  • NC_000021.8:g.34960866T>G
  • NM_017613.2:c.82A>C
  • NM_017613.3:c.82A>C
Protein change:
S28R
Links:
OMIM: 611428.0004; dbSNP: rs768071555
NCBI 1000 Genomes Browser:
rs768071555
Molecular consequence:
  • NM_017613.4:c.82A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Microcephaly, short stature, and limb abnormalities
Identifiers:
MONDO: MONDO:0060533; MedGen: C4539873; OMIM: 617604

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002766782Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely benign
(Mar 31, 2022) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE, Papadopoulos DK, Leitch A, Murina O, Tarnauskaitė Ž, Wessel SR, Zlatanou A, Vernet A, von Kriegsheim A, Mottram RM, Logan CV, Bye H, Li Y, Brean A, Maddirevula S, Challis RC, Skouloudaki K, et al.

Nat Genet. 2017 Apr;49(4):537-549. doi: 10.1038/ng.3790. Epub 2017 Feb 13.

PubMed [citation]
PMID:
28191891
PMCID:
PMC5450907

Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.

Karaca E, Posey JE, Bostwick B, Liu P, Gezdirici A, Yesil G, Coban Akdemir Z, Bayram Y, Harms FL, Meinecke P, Alawi M, Bacino CA, Sutton VR, Kortüm F, Lupski JR.

Am J Med Genet A. 2019 Oct;179(10):2056-2066. doi: 10.1002/ajmg.a.61315. Epub 2019 Aug 13.

PubMed [citation]
PMID:
31407851
PMCID:
PMC6936249
See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766782.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024