ClinVar Miner

Submissions for variant NM_005373.3(MPL):c.775G>A (p.Glu259Lys)

gnomAD frequency: 0.00002  dbSNP: rs528834914
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001820684 SCV002070276 uncertain significance not specified 2020-06-09 criteria provided, single submitter clinical testing DNA sequence analysis of the MPL gene demonstrated a sequence change, c.775G>A, in exon 5 that results in an amino acid change, p.Glu259Lys. This sequence change does not appear to have been previously described in patients with MPL-related disorders and has been described in the gnomAD database in six individuals (dbSNP rs528834914). The p.Glu259Lys change affects a poorly conserved amino acid residue located in a domain of the MPL protein that is known to be functional. The p.Glu259Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu259Lys change remains unknown at this time.
Invitae RCV002542641 SCV003286170 uncertain significance Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia 2022-05-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 259 of the MPL protein (p.Glu259Lys). This variant is present in population databases (rs528834914, gnomAD 0.01%). 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: 1337670). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
GeneDx RCV003229061 SCV003926202 uncertain significance not provided 2022-11-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 31135094)

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