ClinVar Miner

Submissions for variant NM_005373.2(MPL):c.1422G>A (p.Trp474Ter) (rs754859909)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778241 SCV000914409 uncertain significance MPL-Related Disorders 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 thrombocytemia 2019-12-24 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 631606). Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). For these reasons, this variant has been classified as Pathogenic.

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