ClinVar Miner

Submissions for variant NM_000306.4(POU1F1):c.515G>A (p.Arg172Gln)

dbSNP: rs104893765
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521929 SCV000617249 likely pathogenic not provided 2017-09-28 criteria provided, single submitter clinical testing The R172Q variant in the POU1F1 gene has been reported previously in the compound heterozygous and homozygous states in association with combined pituitary hormone deficiency (Turton et al., 2005; Shamseldin et al., 2016). The R172Q variant is observed in 1/66724 (0.002%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The R172Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R172Q as a likely pathogenic variant.
3billion RCV000014584 SCV002521151 likely pathogenic Pituitary hormone deficiency, combined, 1 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POU1F1 related disorder (ClinVar ID: VCV000013614 / PMID: 15928241). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 15928241). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:15928241, 27541381). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323359 SCV004028592 pathogenic Combined pituitary hormone deficiencies, genetic form 2023-07-26 criteria provided, single submitter clinical testing Variant summary: POU1F1 c.515G>A (p.Arg172Gln) results in a conservative amino acid change located in the POU-specific domain (IPR000327) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251290 control chromosomes (gnomAD). c.515G>A has been reported in the literature in two compound heterozygous siblings and in three homozygous siblings affected with Combined Pituitary Hormone Deficiency from two different families (Turton_2005, Shamseldin_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in impaired transactivaton (exhibiting 50% to <10% transactivation activity compared to the WT) at POU-binding sites in the GH-1, PRL, and POU1F1 promoters (Turton_2005). The following publications have been ascertained in the context of this evaluation (PMID: 27541381, 15928241). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000014584 SCV000034838 pathogenic Pituitary hormone deficiency, combined, 1 2005-08-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.