Submissions for variant NM_006261.5(PROP1):c.296G>A (p.Arg99Gln)

gnomAD frequency: 0.00002  dbSNP: rs137853100

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623197	SCV000741438	pathogenic	Inborn genetic diseases	2016-04-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000008574	SCV000800584	uncertain significance	Pituitary hormone deficiency, combined, 2	2017-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851742	SCV002271544	likely pathogenic	not provided	2024-03-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 99 of the PROP1 protein (p.Arg99Gln). This variant is present in population databases (rs137853100, gnomAD 0.02%). This missense change has been observed in individual(s) with combined pituitary hormone deficiency (PMID: 12519826). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8106). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROP1 protein function. Experimental studies have shown that this missense change affects PROP1 function (PMID: 12519826). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317030	SCV004021046	pathogenic	Combined pituitary hormone deficiencies, genetic form	2023-06-28	criteria provided, single submitter	clinical testing	Variant summary: PROP1 c.296G>A (p.Arg99Gln) results in a conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251260 control chromosomes (gnomAD). c.296G>A has been reported in the literature in two homozygous siblings affected with Combined Pituitary Hormone Deficiency (Vieira_2003, Vieira_2007). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in a significant decrease in DNA binding and transactivation activity (Vieira_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12519826, 18157385, 27013732). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence details for independent evaluation, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1), or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000008574	SCV004206529	likely pathogenic	Pituitary hormone deficiency, combined, 2	2023-11-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000008574	SCV005671611	likely pathogenic	Pituitary hormone deficiency, combined, 2	2024-04-25	criteria provided, single submitter	clinical testing
OMIM	RCV000008574	SCV000028782	pathogenic	Pituitary hormone deficiency, combined, 2	2003-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000008574	SCV001452802	pathogenic	Pituitary hormone deficiency, combined, 2	2020-09-16	no assertion criteria provided	clinical testing