rs61755783
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000322.5(PRPH2):c.424C>T(p.Arg142Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,030 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. R142Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000322.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRPH2 | NM_000322.5 | c.424C>T | p.Arg142Trp | missense_variant | 1/3 | ENST00000230381.7 | |
PRPH2 | XR_007059288.1 | n.687C>T | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRPH2 | ENST00000230381.7 | c.424C>T | p.Arg142Trp | missense_variant | 1/3 | 1 | NM_000322.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251422Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135902
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727248
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74326
ClinVar
Submissions by phenotype
not provided Pathogenic:6Other:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2023 | Considered a founder variant in individuals from the southeastern region of the Netherlands (Boon et al., 2009); Identified in individuals with autosomal dominant retinitis pigmentosa (Neveling et al., 2012; Van Cauwenbergh et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29555955, 34411390, 19243827, 34647987, 34828423, 23891399, 8644804, 22003107, 22334370, 28076437, 17653047, 11139263, 11801511, 19038374, 30910914, 31047497, 30215852, 29155698, 28559085, 30718709, 31456290, 32531846, 31589614, 33846575, 34906036, 33546218) - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 14, 2021 | Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, Johan den Dunnen, Kornelia Neveling, LOVD, Manon Peeters. Comment: Variant observed de novo. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 17, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Patterned macular dystrophy 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Molecular Genetics, University of Zurich | Jan 30, 2021 | - - |
Pathogenic, no assertion criteria provided | research | Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana | Apr 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 15, 2022 | - - |
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 27, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Stargardt disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | NEI Ophthalmic Genomics Laboratory, National Institutes of Health | Jan 07, 2020 | The variant NM_000322.4:c.424C>T in the PRPH2 gene has been previously studied(PMIDs 7875944, 22003107, 22334370, 28559085, 28076437, 29555955, 29155698, 30215852, 30910914). We found this variant in 5 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755783,CM951116). It is present in gnomAD browser (AF 0.0000163). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.424C>T in the PRPH2 gene as a Pathogenic mutation. - |
Pathogenic, no assertion criteria provided | research | Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana | Dec 13, 2022 | - - |
Progressive cone dystrophy (without rod involvement) Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Patterned dystrophy of the retinal pigment epithelium Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | NEI Ophthalmic Genomics Laboratory, National Institutes of Health | Jan 07, 2020 | The variant NM_000322.4:c.424C>T in the PRPH2 gene has been previously studied(PMIDs 7875944, 22003107, 22334370, 28559085, 28076437, 29555955, 29155698, 30215852, 30910914). We found this variant in 5 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755783,CM951116). It is present in gnomAD browser (AF 0.0000163). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.424C>T in the PRPH2 gene as a Pathogenic mutation. - |
Choroidal dystrophy, central areolar 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
PRPH2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 142 of the PRPH2 protein (p.Arg142Trp). This variant is present in population databases (rs61755783, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant pattern dystrophy, mild central areolarchoroidal dystrophy, or other retinal disease (PMID: 8644804, 19038374, 19243827, 28076437, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13183). 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 PRPH2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
maculopathy Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Cone dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | NEI Ophthalmic Genomics Laboratory, National Institutes of Health | Jan 07, 2020 | The variant NM_000322.4:c.424C>T in the PRPH2 gene has been previously studied(PMIDs 7875944, 22003107, 22334370, 28559085, 28076437, 29555955, 29155698, 30215852, 30910914). We found this variant in 5 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755783,CM951116). It is present in gnomAD browser (AF 0.0000163). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.424C>T in the PRPH2 gene as a Pathogenic mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at