rs121917839
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_006261.5(PROP1):c.358C>T(p.Arg120Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006261.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROP1 | NM_006261.5 | c.358C>T | p.Arg120Cys | missense_variant | 3/3 | ENST00000308304.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROP1 | ENST00000308304.2 | c.358C>T | p.Arg120Cys | missense_variant | 3/3 | 1 | NM_006261.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000684 AC: 17AN: 248542Hom.: 0 AF XY: 0.0000595 AC XY: 8AN XY: 134400
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461160Hom.: 0 Cov.: 37 AF XY: 0.0000303 AC XY: 22AN XY: 726804
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74436
ClinVar
Submissions by phenotype
Pituitary hormone deficiency, combined, 2 Pathogenic:5Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 08, 2020 | This variant was identified as compound heterozygous with NM_006261.4:c.301_302del. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Apr 09, 2014 | - - |
not provided, no classification provided | literature only | GeneReviews | - | There are reports of spontaneous puberty with decline of gonadotropic function in individuals with PROP1 variants p.Arg120Cys, p.Phe88Ser, and c.150delA [Flück et al 1998]. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2023 | Published functional studies demonstrate a decreased DNA binding efficiency (PMID: 9462743); 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: 31589614, 12153609, 14614227, 33098107, 9462743, 9768691, 10323394, 17526949) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 120 of the PROP1 protein (p.Arg120Cys). This variant is present in population databases (rs121917839, gnomAD 0.03%). This missense change has been observed in individuals with combined pituitary hormone deficiency (PMID: 9462743, 9768691, 12153609, 17526949). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8095). 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: 9462743). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at