Submissions for variant NM_005373.3(MPL):c.317C>T (p.Pro106Leu)

dbSNP: rs750046020

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255329	SCV000321906	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with abnormal subcellular distribution of receptors and impaired glycosylation (Stockklausner et al, 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28034873, 30553997, 23351976, 31589614, 34308104, 35791502, 31135094, 35112413, 26077850, 28955303, 28979237, 28408900, 30318940, 30996850, 31092065, 30183354, 31808840, 33777803, 28444727, 33712866, 27884173, Mutairi_article_2023, 25538044, 34131895, 19036112)
Invitae	RCV000814672	SCV000955091	pathogenic	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 106 of the MPL protein (p.Pro106Leu). This variant is present in population databases (rs750046020, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive MPL-related conditions (PMID: 19036112, 25538044). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265248). 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) has been performed at Invitae 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. Experimental studies have shown that this missense change affects MPL function (PMID: 25538044). For these reasons, this variant has been classified as Pathogenic.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731468	SCV001984330	likely pathogenic	Thrombocythemia 2	2020-11-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255329	SCV002023507	likely pathogenic	not provided	2023-09-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000255329	SCV002069100	likely pathogenic	not provided	2019-07-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MPL gene demonstrated a sequence change, c.317C>T, in exon 3 that results in an amino acid change, p.Pro106Leu. This sequence change has been described in the EXAC database with a low population frequency of 0.005% (dbSNP rs750046020) and has previously been described in patients with familial thrombocytosis in the homozygous state (El-Harith el-HA, et al., 2009; Stockklausner C, et al., 2012). Heterozygous carriers presented with normal platelet counts or mild thrombocytosis (El-Harith el-HA, et al., 2009; Stockklausner C, et al., 2012). The p.Pro106Leu change affects a highly 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.Pro106Leu substitution.
3billion	RCV002250607	SCV002520973	likely pathogenic	Congenital amegakaryocytic thrombocytopenia	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265248). The variant has been observed in multiple, similarly affected unrelated individuals (PMID: 19036112). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002479991	SCV002800513	likely pathogenic	Congenital amegakaryocytic thrombocytopenia; Primary myelofibrosis; Thrombocythemia 2	2021-08-10	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001731468	SCV004101784	pathogenic	Thrombocythemia 2	2023-11-14	criteria provided, single submitter	clinical testing	MPL, a transmembrane protein receptor, is frequently mutated in myeloproliferative neoplasms including essential thrombocytosis and myelofibrosis. The MPL P106L mutation previously reported as pathogenic/likely pathogenic with strong evidence in ClinVar, The p.Pro106Leu change affects a highly conserved amino acid residue located in a domain of the MPL protein that is known to be functional. In-silico pathogenicity prediction tools, The presence of a MPL P106L mutation strongly supports a diagnosis of essential thrombocythemia.This variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004542964	SCV004770411	pathogenic	MPL-related disorder	2024-02-15	criteria provided, single submitter	clinical testing	The MPL c.317C>T variant is predicted to result in the amino acid substitution p.Pro106Leu. This variant has a minor allele frequency of up to 2.6% in Saudi Arabians (Abouelhoda et al. 2016. PubMed ID: 27884173. Table S5), and is a frequent MPL pathogenic variant in the Arab population, leading to thrombocytosis in homozygotes and occasionally mild thrombocytosis in some heterozygous carriers (El-Harith et al. 2009. PubMed ID: 19036112). Functional analyses suggest that the MPL p.Pro106Leu change causes thrombocytosis due to an incomplete trafficking defect (Stockklausner et al. 2015. PubMed ID: 25538044). Expression of the variant MPL protein in vivo in mice partially reproduced the phenotype observed in homozygous patients (Favale et al. 2016. PubMed ID: 28034873). This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992253	SCV004810068	likely pathogenic	Congenital amegakaryocytic thrombocytopenia 1	2024-04-04	criteria provided, single submitter	clinical testing