Submissions for variant NM_000306.4(POU1F1):c.370A>G (p.Met124Val)

gnomAD frequency: 0.00183  dbSNP: rs143373007

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000286336	SCV000446381	uncertain significance	Combined Pituitary Hormone Deficiency, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000727655	SCV000617041	uncertain significance	not provided	2020-08-20	criteria provided, single submitter	clinical testing	Identified in a patient in published literature (Zhang et al., 2019) with septo-optic dysplasia and familial exudative vitreoretinopathy who also had a variant in another gene that might contribute to the phenotype; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31755341)
Eurofins Ntd Llc (ga)	RCV000727655	SCV000854959	uncertain significance	not provided	2018-06-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764516	SCV000895598	uncertain significance	Pituitary hormone deficiency, combined, 1	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727655	SCV001034041	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000764516	SCV003809807	uncertain significance	Pituitary hormone deficiency, combined, 1	2022-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000523099	SCV004020548	benign	not specified	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: POU1F1 c.370A>G (p.Met124Val) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 282674 control chromosomes (gnomAD), predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 115 fold of the estimated maximal expected allele frequency for a pathogenic variant in POU1F1 causing Combined Pituitary Hormone Deficiency (2.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.370A>G has been reported co-occuring with a VUS BCORL1 variant (ClinVar:386901) in the literature in one individual with Septo-optic dysplasia (de Morsier syndrome), which includes hypopituitarism (Zhang_2019). This report does not provide unequivocal conclusions about association of the variant with Combined Pituitary Hormone Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31755341). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000523099	SCV000805017	uncertain significance	not specified	2009-02-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003912463	SCV004730928	likely benign	POU1F1-related disorder	2019-07-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).