Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002629061 | SCV003517196 | uncertain significance | Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia | 2022-03-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 75 of the MPL protein (p.Arg75His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MPL-related conditions. 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. |
Genetic Services Laboratory, |
RCV003151449 | SCV003839727 | uncertain significance | not specified | 2022-05-11 | no assertion criteria provided | clinical testing | DNA sequence analysis of the MPL gene demonstrated a sequence change, c.224G>A, in exon 3 that results in an amino acid change, p.Arg75His. This sequence change does not appear to have been previously described in individuals with MPL-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.020% in the African American subpopulation (dbSNP rs148276667). The p.Arg75His change affects a moderately conserved amino acid residue located in a domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg75His substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg75His change remains unknown at this time. |