rs104894671
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000554.6(CRX):c.239A>C(p.Glu80Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E80G) has been classified as Pathogenic.
Frequency
Consequence
NM_000554.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRX | NM_000554.6 | c.239A>C | p.Glu80Ala | missense_variant | 3/4 | ENST00000221996.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRX | ENST00000221996.12 | c.239A>C | p.Glu80Ala | missense_variant | 3/4 | 2 | NM_000554.6 | P1 | |
CRX | ENST00000613299.1 | c.100+1838A>C | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2023 | Published functional studies demonstrate a damaging effect on photoreceptor development (Terrell et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27013732, 36778408, Sun[MeetingAbstract]2022, 37181651, 11971869, 24888636, 10967037, 12215455, 9390563, 9792858, 22113834, 31626798) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Cone-rod dystrophy 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 14, 1997 | - - |
Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CRX function (PMID: 11971869). 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 CRX protein function. ClinVar contains an entry for this variant (Variation ID: 7416). This missense change has been observed in individual(s) with autosomal dominant cone-rod dystrophy (PMID: 9390563). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 80 of the CRX protein (p.Glu80Ala). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at