Submissions for variant NM_005373.3(MPL):c.224G>A (p.Arg75His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002629061	SCV003517196	uncertain significance	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2024-10-29	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. ClinVar contains an entry for this variant (Variation ID: 2198013). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MPL 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.
Genetic Services Laboratory, University of Chicago	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.