20-5314116-C-T
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM5PP5BP4BS1_SupportingBS2
The NM_144773.4(PROKR2):c.254G>A(p.Arg85His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85G) has been classified as Uncertain significance.
Frequency
Consequence
NM_144773.4 missense
Scores
Clinical Significance
Conservation
Publications
- hypogonadotropic hypogonadism 3 with or without anosmiaInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- hypogonadotropic hypogonadismInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Kallmann syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- septooptic dysplasiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PROKR2 | ENST00000678254.1 | c.254G>A | p.Arg85His | missense_variant | Exon 2 of 3 | NM_144773.4 | ENSP00000504128.1 | |||
| PROKR2 | ENST00000217270.4 | c.254G>A | p.Arg85His | missense_variant | Exon 2 of 3 | 1 | ENSP00000217270.3 | |||
| PROKR2 | ENST00000678059.1 | c.146G>A | p.Arg49His | missense_variant | Exon 2 of 3 | ENSP00000503366.1 |
Frequencies
GnomAD3 genomes 0.000828 AC: 126AN: 152154Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000712 AC: 179AN: 251490 AF XY: 0.000736 show subpopulations
GnomAD4 exome AF: 0.00119 AC: 1733AN: 1461876Hom.: 1 Cov.: 34 AF XY: 0.00116 AC XY: 845AN XY: 727244 show subpopulations
Age Distribution
GnomAD4 genome 0.000828 AC: 126AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000915 AC XY: 68AN XY: 74316 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 3 with or without anosmia Pathogenic:7Uncertain:4
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene (PMID:18826963). (N) 0104 - Dominant Negative is a mechanism of disease for this gene (PMID:29161432). (N) 0108 - This gene is known to be associated with both recessive and dominant disease, where recessive is more penetrant and severe (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance for heterozygous carriers (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. THis variant is in exon 2 of the PROKR2 gene. (N) 0251 - Variant is heterozygous. (N) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (166 heterozygote, 2 homozygotes). (N) 0310 - Variant is present in gnomAD >=0.001 and 0.01 for a dominant condition (212 heterozygote, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (7 transmembrane receptor; PDB). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Alternative changes (p.Arg85Leu, p.Arg85Gly) have been reported as likely benign but mostly pathogenic (ClinVar, PMID:29161432, PMID:20022991, PMID:31093944) in patients with Kallman syndrome. An additional alternative change (p.Arg85Cys) (P) 0802 - Moderate previous evidence of pathogenicity. This variant has been described as both VUS and pathogenic (ClinVar, LOVD). However, it has been reported in multiple unrelated heterozygous patients as well as a homozygote patient, with Kallman syndrome (PMID:29161432, PMID:17054399, PMID:22466334). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional analysis showed a significant reduction in calcium mobilization, MAPK signal activation and whole cell protein expression (PMID:18826963, PMID: 18682503). (P) 1208 – Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
The PROKR2 c.254G>A (p.Arg85His) variant has been reported in heterozygous and homozygous states in multiple individuals affected by several phenotypes, including septo-optic dysplasia (SOD), combined pituitary hormone deficiency (CPHD), hypopituitarism with pituitary stalk interruption, Kallmann syndrome, anosmia, and hypothalamic amenorrhea (Caronia LM et al., PMID: 21247312; Dode C et al., PMID: 23596439; Moya-Plana A PMID: 23082007; Raivio T et al., PMID: 22319038; Reynaud R et al., PMID: 22466334; Sarfati J et al., PMID: 20022991). This variant has been reported to segregate with disease in three families with incomplete penetrance (Caronia LM et al., PMID: 21247312). In one individual, this variant was reported to segregate with a variant in another gene associated with pituitary hormone deficiency (Raivio T et al., PMID: 22319038). This variant has been reported in the ClinVar database as a pathogenic variant by six submitters, likely pathogenic variant by seven submitters, and as a variant of uncertain significance significance by seven submitters (Variation ID: 3451). The highest population minor allele frequency in the Genome Aggregation Database (v.2.1.1) is 0.1246% in the European non-Finnish population. Computational predictors are uncertain regarding the impact of this variant on PROKR2 function. However, functional studies showed that the variant impairs Gq-dependent signaling activity and decreases PROKR2 expression, indicating that this variant impacts protein function (Caronia LM et al., PMID: 21247312; Cox KH et al., PMID: 29161432; Reynaud R et al., PMID: 22466334). Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
_x000D_ Criteria applied: PS3, PM5
This variant has been previously reported in the literature in association with a range of phenotypes that include septo-optic dysplasia (SOD), combined pituitary hormone deficiency (CPHD), hypothalamic amenorrhea, Hypopituitarism with pituitary stalk interruption, Hirschsprung disease, and Kallman syndrome (PMID: 22319038, 21247312, 21858136, 22466334, 20022991, 17054399, 30487145). Inheritance studies showed that the c.254G>A (p.Arg85His) variant is often inherited from an unaffected parent and/or detected in other unaffected family members, which suggests incomplete penetrance (PMID: 21247312, 22466334). Additionally, one individual was reported with the c.254G>A (p.Arg85His) variant and another variant in a gene associated with pituitary hormone deficiency (PMID: 22319038). Functional studies showed that the presence of this variant resulted in a mild damaging effect on receptor signaling activity (PMID: 21247312, 24830383, 29161432, 18826963). However, recent functional studies suggest the c.254G>A (p.Arg85His) variant is only damaging in the homozygous state (PMID: 29161432). A different nucleotide change at the same position (c.254G>T, p.Arg85Leu) has been reported as a heterozygous change in individuals with Kallman syndrome, combined pituitary hormone deficiency, GH deficiency, TSH deficiency and ACTH deficiency affected individuals (PMID: 23386640, 20022991). The c.254G>A (p.Arg85His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.075% (212/282884) and is absent in the homozygous state. The c.254G>A (p.Arg85His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.254G>A (p.Arg85His) variant is classified as Likely Pathogenic.
not provided Pathogenic:2Uncertain:3
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 85 of the PROKR2 protein (p.Arg85His). This variant is present in population databases (rs74315418, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive Kallmann syndrome and/or autosomal dominant combined pituitary hormone deficiency (PMID: 17054399, 33098107, 37432431). ClinVar contains an entry for this variant (Variation ID: 3451). Invitae Evidence 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 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 PROKR2 protein function. Experimental studies have shown that this missense change affects PROKR2 function (PMID: 18826963, 22745195, 24830383, 29161432). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Published functional studies demonstrate impaired G-protein signaling (PMID: 18826963, 24830383); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21247312, 23643382, 21858136, 24830383, 22745195, 22319038, 26207952, 22466334, 29161432, 32870266, 34198905, 30487145, 28807454, 34426522, 33775534, 35669683, 33098107, 17054399, 36694982, 31093944, 35236788, 18682503, 37122876, 37321569, 37019085, 37338295, 20022991, 18826963, 37432431, 30476936, 30921766, 37540677, 38593951, 39408606, 39719010, 38556123, 38614076)
Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1
Hypogonadism with anosmia Pathogenic:1
This is a recurrent pathogenic variant that is known to exhibit incomplete penetrance and variable expressivity. This change has been reported in individuals with Kallmann syndrome (KS), normosmic isolated gonadotropin-releasing hormone deficiency (IGD), anosomia, hypopituitarism, and hypothalamic amenorrhea; but is also present in many phenotypically normal individuals (PMID: 23596439, PMID: 20022991, PMID: 21247312, PMID: 22319038, PMID: 22466334, PMID: 23082007, PMID: 23643382). The c.254G>A variant, located in exon 2 of PROKR2, substitutes the arginine with histidine at position 85 of the protein. This variant is found in individuals with European ancestry with an allele frequency of ~0.12% (161/129,188 alleles) in the Genome Aggregation Database. This frequency is due to a common founder allele (PMID: 26207952). The p.Arg85His change has been demonstrated to cause a loss of function in in vitro assays (PMID: 18826963, PMID: 29161432).
PROKR2-related disorder Pathogenic:1
The PROKR2 c.254G>A variant is predicted to result in the amino acid substitution p.Arg85His. This variant has been reported in the heterozygous and homozygous states in many individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Dodé et al 2006. PubMed ID: 17054399; Sarfati et al. 2010. PubMed ID: 20022991; Table S3, Miraoui et al. 2013. PubMed ID: 23643382; Choi et al. 2015. PubMed ID: 26207952; Hacquart et al. 2017. PubMed ID: 28807454; Kałużna et al. 2021. PubMed ID: 34198905; Cho et al. 2021. PubMed ID: 33775534). This variant has also been reported in individuals with hypopituitarism and hypothalamic amenorrhea (Reynaud et al. 2012. PubMed ID: 22466334; Jullien et al. 2020. PubMed ID: 33098107; Caronia et al. 2011. PubMed ID: 21247312; Delaney et al. 2020. PubMed ID: 32870266). Functional studies showed that this variant impairs Gq-dependent signaling activity and decreases PROKR2 expression when tested alone, but when co-transfected with wild type, only 2 of 3 signaling assays showed loss of function (Monnier et al. 2009. PubMed ID: 18826963; Caronia et al. 2011. PubMed ID: 21247312; Reynaud et al. 2012. PubMed ID: 22466334; Cox et al. 2018. PubMed ID: 29161432). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-5294762-C-T), and is present in asymptomatic family members (Caronia et al. 2011. PubMed ID: 21247312; Reynaud et al. 2012. PubMed ID: 22466334). Based on the available evidence, this variant is classified as likely pathogenic.
not specified Uncertain:1
Variant summary: PROKR2 c.254G>A (p.Arg85His) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00071 in 251490 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European 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.254G>A has been observed in multiple individuals affected with clinical features of Kallmann Syndrome in both the heterozygous and biallelic state (e.g. Monnier_2009, Cox_2018, Sarfati_2013, Dod_2006, Kardelen_2023, Poch_2024, Toni_2024). These data indicate that the variant is likely to be associated with disease. At least three publication reports experimental evidence evaluating an impact on protein function and interferes only modestly with receptor function (Monnier_2009, Abreu_2012, Reynaud_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22745195, 29161432, 17054399, 37338295, 18826963, 38593951, 22466334, 24031091, 37019085). ClinVar contains an entry for this variant (Variation ID: 3451). Based on the evidence outlined above, the variant was classified as uncertain significance.
Amenorrhea Uncertain:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at