6-42704568-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000322.5(PRPH2):c.625G>A(p.Val209Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,032 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V209D) has been classified as Pathogenic.
Frequency
Consequence
NM_000322.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251412Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135900
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727244
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 06, 2019 | DNA sequence analysis of the PRPH2 gene demonstrated a sequence change, c.625G>A, in exon 2 that results in an amino acid change, p.Val209Ile. The p.Val209Ile change affects a highly conserved amino acid residue located in a domain of the PRPH2 protein that is known to be functional. The p.Val209Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change was identified in a 51 year old male with adult onset foveomacular vitelliform dystrophy (bilateral); it was absent in 100 controls (PMID: 20213611). It was also reported in a patient with early-onset high myopia (PMID: 29453956). Functional studies have shown that the p.Val209Ile change results in increased splicing and protein expression (PMID: 26796962). Different sequence changes affecting the same amino acid residue (p.Val209Phe and p.Val209Asp) have also been described in patients with macular and cone-rod dystrophy (PMID: 28041643 and PMID: 29555955). This sequence change has been described in the gnomAD database with a low population frequency of 0.0028% (dbSNP rs753657349). The p.Val209Ile amino acid change occurs in a region of the PRPH2 gene where other missense sequence changes have been described in patients with ocular disorders including retinitis pigmentosa, foveamacular dystrophy, and central areolar choroidal dystrophy (PMID: 20213611). These collective evidences indicate that this sequence change is likely pathogenic. - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Apr 06, 2021 | Curator: Global Variome, with Curator vacancy. Submitters to LOVD: LOVD, Manon Peeters. Comment: Variant observed de novo. - |
Retinitis pigmentosa 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PRPH2 related disorder (ClinVar ID: VCV001067264). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001067308, PMID:29555955). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.631>=0.6, 3CNET: 0.941>=0.75). A missense variant is a common mechanism associated with Retinitis pigmentosa 7 and digenic form. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000317). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
PRPH2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 01, 2022 | This missense change has been observed in individual(s) with clinical features of autosomal dominant macular dystrophy (PMID: 20213611). This variant is present in population databases (rs753657349, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 209 of the PRPH2 protein (p.Val209Ile). ClinVar contains an entry for this variant (Variation ID: 1067264). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val209 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29555955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at