Submissions for variant NM_000460.4(THPO):c.791_794del (p.Pro264fs)

dbSNP: rs760659440

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779403	SCV000916014	uncertain significance	Thrombocythemia 1	2017-09-07	criteria provided, single submitter	clinical testing	The THPO c.791_794delCCTC (p.Pro264HisfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. It 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 and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for essential thrombocythemia.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003718288	SCV004507888	uncertain significance	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro264Hisfs*5) in the THPO gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the THPO protein. This variant is present in population databases (rs760659440, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with THPO-related conditions. ClinVar contains an entry for this variant (Variation ID: 632414). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003718288	SCV004847441	uncertain significance	not provided	2024-02-16	criteria provided, single submitter	clinical testing	The p.Leu226ArgfsX89 variant in THPO has not been previously reported in individuals with familial thrombocytopenia but has been identified in 0.021% (253/1180012) of non-Finnish European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 632414). Loss-of-function variants in the THPO gene have been reported in individuals with autosomal dominant thrombocytopenia or autosomal recessive congenital amegakaryocytic thrombocytopenia. While this variant is predicted to cause a frameshift, THPO transcripts utilize two alternative reading frames in the last exon, and loss-of-function variants in this exon are frequent in the general population. Furthermore, there is moderate evidence for the association between THPO variants and familial thrombocytopenia. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: none.