rs764256655
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_201253.3(CRB1):c.584G>T(p.Cys195Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,092 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. C195W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_201253.3 missense
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 |
---|---|---|---|---|---|---|---|
CRB1 | NM_201253.3 | c.584G>T | p.Cys195Phe | missense_variant | 2/12 | ENST00000367400.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRB1 | ENST00000367400.8 | c.584G>T | p.Cys195Phe | missense_variant | 2/12 | 1 | NM_201253.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251300Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461864Hom.: 0 Cov.: 33 AF XY: 0.0000426 AC XY: 31AN XY: 727232
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
Leber congenital amaurosis 8 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 27, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2018 | The C195F variant in the CRB1 gene has been reported previously in association with autosomal recessive CRB1-related disorder, in affected individuals who were compound heterozygous for the C195F variant and another pathogenic variant (den Hollander et al., 2004; Morarji et al., 2016). The C195F variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The C195F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret C195F as a likely pathogenic variant. - |
Retinitis pigmentosa 12 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Retinitis pigmentosa 12;C1868310:Pigmented paravenous retinochoroidal atrophy;C3151202:Leber congenital amaurosis 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 26, 2021 | - - |
Macular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Molecular Medicine, University of Leeds | Oct 27, 2017 | - - |
Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 195 of the CRB1 protein (p.Cys195Phe). This variant is present in population databases (rs764256655, gnomAD 0.004%). This missense change has been observed in individual(s) with CRB1-related disease (PMID: 15459956, 26914788, 27096895, 29391521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265083). 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 CRB1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 25, 2019 | - - |
Pigmented paravenous retinochoroidal atrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at