Submissions for variant NM_005373.3(MPL):c.1422G>A (p.Trp474Ter)

gnomAD frequency: 0.00003  dbSNP: rs754859909

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778241	SCV000914409	uncertain significance	MPL-related disorder	2018-12-26	criteria provided, single submitter	clinical testing	This variant is a stop-gained variant predicted to result in premature termination of the protein. The variant was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Invitae	RCV001055113	SCV001219483	pathogenic	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp474*) in the MPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). This variant is present in population databases (rs754859909, gnomAD 0.006%). 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: 631606). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001816834	SCV002067318	pathogenic	not provided	2019-12-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MPL gene demonstrated a sequence change, c.1422G>A which results in the creation of a premature stop codon at amino acid position 474, p.Trp474*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MPL protein with potentially abnormal function. This sequence change has not been previously described in a patient with MPL-related disorders. Truncating pathogenic variants are well described in the MPL gene and have been observed in several patients with congenital amegakaryocytic thrombocytopenia. Truncating pathogenic variants both downstream and upstream of the c.1422G>A (p.Trp474*) variant have been described in patients with congenital amegakaryocytic thrombocytopenia. This sequence change has been described in the gnomAD database with a low population frequency of 0.0058% in non-Finnish subpopulation (5 individuals in gnomAD) (dbSNP rs754859909). These evidences suggest this variant to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000778241	SCV004109860	likely pathogenic	MPL-related disorder	2023-05-13	criteria provided, single submitter	clinical testing	The MPL c.1422G>A variant is predicted to result in premature protein termination (p.Trp474*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-43814627-G-A). Nonsense variants in MPL are expected to be pathogenic. This variant is interpreted as likely pathogenic.