ClinVar Miner

Submissions for variant NM_033100.4(CDHR1):c.783G>A (p.Pro261=) (rs147346345)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000369498 SCV000365411 uncertain significance Cone-Rod Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487554 SCV000574853 pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000487554 SCV000617830 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing The c.783 G>A variant in the CDHR1 gene has been reported in the compound heterouzygous state in a a patient with sporadic retinitis pigmentosa (Glockle et al., 2014). The c.783 G>A variant is observed in 376/66728 (0.5%) alleles from individuals of non-Finnish European background in the ExAC dataset, including one homozygote (Lek et al., 2016). Although the c.783 G>A (P261=) variant results in a synonymous amino acid substitution, splice algorithms predict this variant destroys the natural splice donor site in intron 8, which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of c.783 G>A in this individual is unknown. We interpret c.783 G>A as a variant of uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000487554 SCV000701570 uncertain significance not provided 2016-10-27 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000625429 SCV000745341 uncertain significance Cone-rod dystrophy 15 2017-06-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825304 SCV000966599 uncertain significance not specified 2018-12-19 criteria provided, single submitter clinical testing The c.783G>A (p.Pro261Pro) variant in CDHR1 has been reported in 3 homozygous an d 3 compound heterozygous individuals with retinitis pigmetosa, as well as a het erozygous variant in one individual with an altenative cause of disease (Glockle 2013, Tiwari 2016, Haer-Wigman 2017, Stingl 2017, Bessette 2018). This variant has been identified in 0.6% (148/25122) of Finnish chromosomes, including 3 homo zygotes, by gnomAD (http://gnomad.broadinstitute.org).This variant is located in the last base of the exon, which is part of the 5? splice region. Computational tools suggest an impact to splicing; however, this information is not predictiv e enough to determine pathogenicity. Funcitonal studies suggest this variant lea ds to skipping of exon 8; however, these assays may not accurately represent bio logical function. In summary, due to conflicting data, the clinical significance of the p.Pro261Pro variant is uncertain. ACMG/AMP criteria applied: PM3, PS4_Mo derate, PS3_Supporting, BS1_Supporting, BP5.
Invitae RCV000487554 SCV001038155 benign not provided 2020-12-03 criteria provided, single submitter clinical testing
Mendelics RCV000625429 SCV001138101 uncertain significance Cone-rod dystrophy 15 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283008 SCV001159162 uncertain significance none provided 2019-12-27 criteria provided, single submitter clinical testing The CDHR1 c.783G>A; p.Pro261Pro variant is reported in the literature in multiple individuals with retinitis pigmentosa or a related retinopathy (Bessette 2018, Birtel 2018, Glockle 2014, Haer-Wigman 2017, Stingl 2017). Multiple affected individuals with this variant were either homozygous or carried a second CDHR1 variant (Bessette 2018, Birtel 2018, Glockle 2014, Stingl 2017). However, the c.783G>A variant is also found in the general population with an overall allele frequency of 0.31% (863/282802 alleles, including four homozygotes) in the Genome Aggregation Database. This is a synonymous variant in the last nucleotide of exon 8, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Indeed, a minigene splicing assay in cultured cells indicates this variant leads to exon 8 skipping, which causes an in-frame deletion of 48 amino acids, although it is unclear if the extent of exon skipping in retinal tissues is clinically significant (Stingl 2017). Due to conflicting and limited information, the clinical significance of the c.783G>A variant is uncertain at this time. References: Bessette AP et al. Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene and a review of the literature. Ophthalmic Genet. 2018 Jan-Feb;39(1):51-55. Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824. Glockle N et al. Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. Eur J Hum Genet. 2014 Jan;22(1):99-104. Haer-Wigman L et al. Diagnostic exome sequencing in 266 Dutch patients with visual impairment. Eur J Hum Genet. 2017 May;25(5):591-599. Stingl K et al. CDHR1 mutations in retinal dystrophies. Sci Rep. 2017 Aug 1;7(1):6992.
Blueprint Genetics RCV000787811 SCV001238981 uncertain significance Retinal dystrophy 2019-02-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000625429 SCV001370120 likely pathogenic Cone-rod dystrophy 15 2019-12-04 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,PP3,BS1. This variant was detected in homozygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV000625429 SCV001440752 likely pathogenic Cone-rod dystrophy 15 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000487554 SCV001446677 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV000625429 SCV001548024 likely pathogenic Cone-rod dystrophy 15 2021-01-30 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001723886 SCV001950224 likely pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Pro261= variant in CDHR1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787811 SCV000926821 likely pathogenic Retinal dystrophy 2018-04-01 no assertion criteria provided research

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