rs121918563
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000322.5(PRPH2):āc.554T>Cā(p.Leu185Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000322.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRPH2 | NM_000322.5 | c.554T>C | p.Leu185Pro | missense_variant | 1/3 | ENST00000230381.7 | NP_000313.2 | |
PRPH2 | XR_007059288.1 | n.817T>C | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRPH2 | ENST00000230381.7 | c.554T>C | p.Leu185Pro | missense_variant | 1/3 | 1 | NM_000322.5 | ENSP00000230381 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251406Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135888
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727240
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Patterned macular dystrophy 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The PRPH2 c.554T>C variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2013 | - - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2017 | The L185P variant was reported in 3 families where it functioned as a recessive variant only resultingin a disease phenotype when inherited with a null (loss-of-function) variant in the ROM1 gene ( Kajiwaraet al. 1994). Therefore the L185P variant in the PRPH2 gene and a null variant in the ROM1 genecause a digenic form of retinitis pigmentosa. The L185P substitution has also been reported previously as anapparently homozygous variant in association with Leber congenital amaurosis (Wang et al., 2013). TheL185P variant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The L185P variant is a semi-conservative amino acid substitution that occurs at a positionthat is conserved across species. In silico analysis predicts this substitution is probably damaging to theprotein structure/function. Therefore, L185P is interpreted to be a pathogenic variant. - |
not provided, no classification provided | literature only | Retina International | - | - - |
Patterned dystrophy of the retinal pigment epithelium Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | NEI Ophthalmic Genomics Laboratory, National Institutes of Health | Jan 07, 2020 | The variant NM_000322.4:c.554T>C in the PRPH2 gene has been previously studied(PMIDs 1684223, 8202715, 10800708, 12925772). We found this variant in 1 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs121918563,CM910323). It is present in gnomAD browser (AF 0.00000812). It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PP1-M, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.554T>C in the PRPH2 gene as a Likely Pathogenic mutation. - |
Retinitis pigmentosa 7, digenic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2013 | - - |
Leber congenital amaurosis 18 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2013 | - - |
PRPH2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 15, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 8943002, 11297544, 11427722, 12925772). 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) performed at Invitae indicates that this missense variant is expected to disrupt PRPH2 protein function. ClinVar contains an entry for this variant (Variation ID: 13165). This missense change has been observed in individuals with autosomal recessive and autosomal dominant retinal dystrophy. This variant may be associated with a milder, later-onset form of autosomal dominant retinal dystrophy (PMID: 1684223, 8202715, 9331261, 16799052, 23847139, 26720483, 32531846; Invitae). This variant is present in population databases (rs121918563, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 185 of the PRPH2 protein (p.Leu185Pro). - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 19, 2018 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Apr 06, 2021 | Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Feng Wang, Julia Lopez, Manon Peeters. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at