rs121918567
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000322.5(PRPH2):c.584G>T(p.Arg195Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R195P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000322.5 missense, splice_region
Scores
Clinical Significance
Conservation
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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.584G>T | p.Arg195Leu | missense_variant, splice_region_variant | 2/3 | ENST00000230381.7 | |
PRPH2 | XR_007059288.1 | n.1029G>T | splice_region_variant, non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRPH2 | ENST00000230381.7 | c.584G>T | p.Arg195Leu | missense_variant, splice_region_variant | 2/3 | 1 | NM_000322.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251036Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135754
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152278Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74464
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Likely pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Apr 06, 2021 | Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters. Comment: Variant observed de novo. - |
Choroidal dystrophy, central areolar 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2003 | - - |
PRPH2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2022 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 195 of the PRPH2 protein (p.Arg195Leu). This variant is present in population databases (rs121918567, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg195 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25082885; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 26796962). 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 (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 13182). This missense change has been observed in individuals with autosomal dominant choroidal dystrophy (PMID: 14557183, 20213611). It has also been observed to segregate with disease in related individuals. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at