Submissions for variant NM_006261.5(PROP1):c.301_302del (p.Leu102fs)

dbSNP: rs193922688

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030379	SCV000053046	pathogenic	Combined pituitary hormone deficiencies, genetic form	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Illumina Laboratory Services, Illumina	RCV000008566	SCV000456757	pathogenic	Pituitary hormone deficiency, combined, 2	2017-09-13	criteria provided, single submitter	clinical testing	The PROP1 c.301_302delAG (p.Leu102CysfsTer8) variant results in a frameshift and is predicted to result in premature termination of the protein and loss of the DNA-binding homeodomain and C-terminal transactivation domain (Wu et al. 1998). Across a selection of the available literature, the p.Leu102CysfsTer8 variant has been reported in a total of 280 individuals with combined pituitary hormone deficiency, including 213 homozygotes, 64 compound heterozygotes, and three heterozygotes in whom a second variant was not been identified (Wu et al. 1998; Cogan et al. 1998; Fofanova et al. 1998; Deladoey et al. 1999; Mendonca et al. 1999; Pernasetti et al. 2000; Riepe et al. 2001; Lee et al. 2004; Avbelj Stefanija et al. 2015; Lazea et al. 2015; Dusatkova et al. 2016). The p.Leu102CysfsTer8 variant was shown to segregate with disease in a four-generation family (Pernasetti et al. 2000). The variant was absent from 193 controls but is reported at a frequency of 0.00109 in the European American population of the Exome Sequencing Project. Based on the collective evidence and the potential impact of frameshift variants, the p.Leu102CysfsTer8 variant is classified as pathogenic for combined pituitary hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Athena Diagnostics	RCV000517269	SCV000614793	pathogenic	not provided	2012-12-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000517269	SCV000854930	pathogenic	not provided	2017-08-28	criteria provided, single submitter	clinical testing
Invitae	RCV000517269	SCV000961893	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu102Cysfs*8) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 125 amino acid(s) of the PROP1 protein. This variant is present in population databases (rs193922688, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with combined pituitary hormone deficiency in many families and it has been observed in combination with another PROP1 variant in unrelated individuals with this condition (PMID: 9462743, 11081182, 16735499, 17162714, 26111865, 28734020). It has also been observed to segregate with disease in related individuals. This variant is also known as A301G302 deletion and delGA296 (S109X). ClinVar contains an entry for this variant (Variation ID: 8098). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PROP1 function (PMID: 9462743). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000008566	SCV001162986	pathogenic	Pituitary hormone deficiency, combined, 2		criteria provided, single submitter	clinical testing
GeneDx	RCV000517269	SCV001167827	pathogenic	not provided	2020-06-24	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 125 amino acids are replaced with 7 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Published functional studies demonstrate a damaging effect on DNA binding and transactivation function (Wu et al., 1998); This variant is associated with the following publications: (PMID: 28734020, 12414875, 16984240, 17526936, 15472175, 10084575, 25581745, 30959475, 31948187, 31090814, 31093944, 32415500, 11081182, 26111865, 10323394, 9745452, 15126542, 10634415, 26059845, 17162714, 16735499, 16703408, 18157385, 11022176, 9462743, 11549674, 30266296, 31589614)
Myriad Genetics, Inc.	RCV000008566	SCV001194082	pathogenic	Pituitary hormone deficiency, combined, 2	2019-11-12	criteria provided, single submitter	clinical testing	NM_006261.4(PROP1):c.301_302delAG(aka L102Cfs*8) is classified as pathogenic in the context of combined pituitary hormone deficiency, PROP1 related. Sources cited for classification include the following: PMID 9462743 and 15126542. Classification of NM_006261.4(PROP1):c.301_302delAG(aka L102Cfs*8) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008566	SCV001934229	likely pathogenic	Pituitary hormone deficiency, combined, 2	2020-10-08	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_006261.4:c.358C>T.
Laan Lab, Human Genetics Research Group, University of Tartu	RCV002254517	SCV002525861	pathogenic	46,XY partial gonadal dysgenesis	2020-08-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000008566	SCV002793657	pathogenic	Pituitary hormone deficiency, combined, 2	2021-12-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000008566	SCV003826671	pathogenic	Pituitary hormone deficiency, combined, 2	2022-06-20	criteria provided, single submitter	clinical testing
OMIM	RCV000008566	SCV000028774	pathogenic	Pituitary hormone deficiency, combined, 2	2004-10-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000008566	SCV001452801	pathogenic	Pituitary hormone deficiency, combined, 2	2020-09-16	no assertion criteria provided	clinical testing
GeneReviews	RCV000008566	SCV002500843	not provided	Pituitary hormone deficiency, combined, 2		no assertion provided	literature only	Common variant in Europe & Latin America [Dusatkova et al 2016]; founder variant in Lithuania [Navardauskaite et al 2014] & Hutterite population [Wu et al 1998]; Impaired gonadotropic function occurs in all individuals with the most common PROP1 variant, c.301_302delAG [Madeira et al 2017].
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000008566	SCV002583491	pathogenic	Pituitary hormone deficiency, combined, 2	2022-06-02	no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000008566	SCV004012819	not provided	Pituitary hormone deficiency, combined, 2		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.