Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Undiagnosed Diseases Network, |
RCV001310228 | SCV001499840 | pathogenic | DONSON-related Meier-Gorlin syndrome | 2020-02-20 | criteria provided, single submitter | clinical testing | |
| Bicknell laboratory, |
RCV001527377 | SCV001738360 | pathogenic | Meier-Gorlin syndrome | criteria provided, single submitter | research | ||
| Labcorp Genetics |
RCV003718401 | SCV004506402 | uncertain significance | not provided | 2023-09-20 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects DONSON function (PMID: 31784481). 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 expected to disrupt DONSON protein function. ClinVar contains an entry for this variant (Variation ID: 1012222). This missense change has been observed in individual(s) with Meier-Gorlin syndrome (PMID: 31784481). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 224 of the DONSON protein (p.Pro224Ser). |
| Victorian Clinical Genetics Services, |
RCV004594271 | SCV005086684 | likely pathogenic | Microcephaly, short stature, and limb abnormalities | 2023-12-21 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. 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 heterozygous for a single DONSON variant (PMID: 31407851). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 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) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed as compound heterozygous in an individual with DONSON-related features in the literature, and was classified as pathogenic by a clinical laboratory in ClinVar in this same individual (PMID: 31784481). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In transfected HeLa cells this variant was shown to have diffuse protein cellular localisation compared to wild type protein which was localised in the nucleus (PMID: 31784481). However, other studies in DONSON depleted cells have shown that this variant was able to rescue the cells' ability to synthesise DNA (PMID: 37638758) (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_017613.3:c.876C>G; p.(Phe292Leu)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |