ClinVar Miner

Submissions for variant NM_000554.6(CRX):c.118C>T (p.Arg40Trp)

gnomAD frequency: 0.00001  dbSNP: rs749738655
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001071559 SCV001236868 pathogenic Leber congenital amaurosis 7; Cone-rod dystrophy 2 2024-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 40 of the CRX protein (p.Arg40Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 26161267, 29785639, 31626798, 32533067). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 864383). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CRX protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075179 SCV001240791 pathogenic Retinal dystrophy 2018-11-02 criteria provided, single submitter clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV001352999 SCV001548091 likely pathogenic Cone-rod dystrophy 2 2021-01-30 criteria provided, single submitter clinical testing
3billion, Medical Genetics RCV001352999 SCV004013475 likely pathogenic Cone-rod dystrophy 2 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000864383 / PMID: 26161267). A different missense change at the same codon (p.Arg40Gln) has been reported to be associated with CRX related disorder (ClinVar ID: VCV000437959 / PMID: 28041643). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx RCV003318660 SCV004022736 likely pathogenic not provided 2023-07-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31626798, 29785639, 32566799, 32533067, 33546218, 35836572, 37239417, 36284460, 32112665, 26161267)
Dept Of Ophthalmology, Nagoya University RCV001075179 SCV004706289 likely pathogenic Retinal dystrophy 2023-10-01 criteria provided, single submitter research

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