Submissions for variant NM_144773.4(PROKR2):c.253C>G (p.Arg85Gly)

dbSNP: rs141090506

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000345795	SCV000434480	likely benign	Hypogonadotropic hypogonadism 3 with or without anosmia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000413366	SCV000490743	pathogenic	not provided	2015-04-23	criteria provided, single submitter	clinical testing	The R85G missense variant in the PROKR2 gene has been reported previously in the heterozygous state inassociation with Kallmann syndrome and related disorders (Sarfati et al., 2010; Raivio et al., 2012). It wasobserved at a low frequency in control individuals in the 1000 Genomes Database and at a low frequency inindividuals of African American ancestry in the NHLBI Exome Sequencing Project. Additionally, multiplevariants have been reported at the R85 residue in the PROKR2 gene (R85C, R85L, R85H) (Stenson, et al.,2009). Therefore, we interpret R85G to be a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413366	SCV001003682	likely benign	not provided	2024-09-24	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000345795	SCV001441329	likely pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2019-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701425	SCV005204404	likely benign	not specified	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: PROKR2 c.253C>G (p.Arg85Gly) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) 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 0.00036 in 251490 control chromosomes, predominantly at a frequency of 0.0053 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PROKR2 causing Kallmann Syndrome 3 phenotype. c.253C>G has been reported in the literature in individuals affected with Kallmann Syndrome, Septo-Optic Dysplasia, also in individuals undertaking hereditary cancer testing or self-identified healthy adult cohort, without strong evidence for causality (Sarfati_2010, Raivio_2012, Berg_2013, Rasouly_2019, Shillington_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Kallmann Syndrome 3. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal signaling activity and expression in HEK29 cells or in vitro (Cox_2018, Raivio_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22995991, 29161432, 22319038, 30476936, 20022991, 37642312). ClinVar contains an entry for this variant (Variation ID: 338864). Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV000345795	SCV005660838	uncertain significance	Hypogonadotropic hypogonadism 3 with or without anosmia	2024-05-23	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000345795	SCV001469210	likely pathogenic	Hypogonadotropic hypogonadism 3 with or without anosmia	2020-05-06	no assertion criteria provided	clinical testing