Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002537729 | SCV003469653 | uncertain significance | Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia | 2022-07-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 238 of the MPL protein (p.Gly238Cys). This variant is present in population databases (rs144210383, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 988820). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. |
| Victorian Clinical Genetics Services, |
RCV003225170 | SCV003921802 | likely pathogenic | Congenital amegakaryocytic thrombocytopenia | 2021-05-07 | criteria provided, single submitter | clinical testing | 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with recessive congenital amegakaryocytic thrombocytopenia (CAMT) (MIM#604498) and dominant thrombocythemia 2 (MIM#601977), respectively (PMIDs: 28955303, 26423830). (I) 0108 - This gene is associated with autosomal dominant and recessive disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated fibronectin type-III 1 domain, and forms a cysteine residue. Cysteine residues in this protein are known to be functionally important (PMID: 28955303, Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS, and observed in a heterozygous individual with a bleeding disorder (ClinVar, PMID: 32935436). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected<i> in trans</i> with a second pathogenic heterozygous variant (p.(Arg102Pro)) 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 |
| Birmingham Platelet Group; University of Birmingham | RCV001270506 | SCV001450805 | uncertain significance | Abnormal bleeding; Thrombocytopenia | 2020-05-01 | no assertion criteria provided | research |