ClinVar Miner

Submissions for variant NM_006261.4(PROP1):c.334C>T (p.Arg112Ter) (rs766673446)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169361 SCV000220732 likely pathogenic Pituitary hormone deficiency, combined 2 2014-09-25 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000169361 SCV000915127 likely pathogenic Pituitary hormone deficiency, combined 2 2017-12-11 criteria provided, single submitter clinical testing The PROP1 c.334C>T (p.Arg112Ter) stop-gained variant has been reported in two studies and is found in a total of three individuals, including one in a homozygous state and two in a compound heterozygous state. The homozygote is a Japanese individual with combined pituitary hormone deficiency (CDPH) (Ogo et al. 2011). The compound heterozygotes are two brothers with ages of onset of four and six; they are reported to present with a milder phenotype of CDPH, whereby central hypothyroidism was the first noted symptom (Ziemnicka et al. 2015). The p.Arg112Ter variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. The variant is in a region of good sequence coverage, so the variant is presumed to be rare. In silico prediction tools suggest that the variant disrupts the paired-like homeodomain that is required for DNA interaction with the PROP1 protein, leading to loss of DNA binding activity, although other studies suggest the protein maintains some functionality (Ziemnicka et al. 2015). Based on the evidence and the potential impact of stop-gained variants, the p.Arg112Ter variant is classified as likely pathogenic for combined pituitary hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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