Submissions for variant NM_005373.3(MPL):c.655C>G (p.Gln219Glu)

gnomAD frequency: 0.00017  dbSNP: rs142737453

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665815	SCV000789994	uncertain significance	Congenital amegakaryocytic thrombocytopenia	2017-03-24	criteria provided, single submitter	clinical testing
Invitae	RCV000796648	SCV000936169	uncertain significance	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 219 of the MPL protein (p.Gln219Glu). This variant is present in population databases (rs142737453, gnomAD 0.03%). 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: 134829). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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.
Illumina Laboratory Services, Illumina	RCV000665815	SCV001253044	uncertain significance	Congenital amegakaryocytic thrombocytopenia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV003407517	SCV004127909	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MPL: BP4
ITMI	RCV000121544	SCV000085738	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000665815	SCV001453976	uncertain significance	Congenital amegakaryocytic thrombocytopenia	2020-09-16	no assertion criteria provided	clinical testing