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

gnomAD frequency: 0.00446  dbSNP: rs147346345

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000369498	SCV000365411	uncertain significance	Cone-Rod Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487554	SCV000574853	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CDHR1: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3
GeneDx	RCV000487554	SCV000617830	uncertain significance	not provided	2024-10-30	criteria provided, single submitter	clinical testing	Observed multiple times with a second CDHR1 variant in unrelated patients with features of a CDHR1-related retinal dystrophy and suggested to represent a hypomorphic variant (PMID: 31387115, 28765526, 32681094, 23591405); Individuals homozygous for c.783G>A had a mild and late-onset macular dystrophy, which may account for the observance of homozygous individuals in large population cohorts (PMID: 28765526, 28885867, 31387115, 34795310, 32681094); Published RNA studies suggest this variant results in a damaging effect with skipping of exon 8 (PMID: 28765526); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 37510321, 35260635, 36259723, 36460718, 37734845, 23591405, 28885867, 28224992, 28765526, 30718709, 34426522, 31387115, 34795310, 32681094, 35836572, 32037395, 29555955, 34327195, 32531858, 38927562, 36837600, 38540785, 33546218)
Eurofins Ntd Llc (ga)	RCV000487554	SCV000701570	uncertain significance	not provided	2016-10-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000487554	SCV001038155	likely pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects codon 261 of the CDHR1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDHR1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs147346345, gnomAD 0.6%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with retinal dystrophy (PMID: 23591405, 28765526, 28885867, 31387115, 32681094, 33546218, 34795310). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 301224). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 28765526, 31387115). 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.
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	RCV000487554	SCV001159162	uncertain significance	not 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	2021-12-08	criteria provided, single submitter	clinical testing	This variant was identified as homozygous._x000D_ Criteria applied: PS3, PS4_MOD, PM3_SUP
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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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.
Molecular Genetics, Royal Melbourne Hospital	RCV000625429	SCV002072635	pathogenic	Cone-rod dystrophy 15	2021-11-11	criteria provided, single submitter	clinical testing	This sequence change is a synonymous (silent) variant in exon 8 of CDHR1 that is predicted to impact splicing (SpliceAI, MaxEntScan). This prediction is confirmed by RT-PCR, RNASeq, and mini-gene assays. The assay demonstrated that the variant impacts splicing by in-frame exon 8 skipping (PMID: 28765526, 31387115). The highest population minor allele frequency in gnomAD v2.1 is 0.5% (633/129,112 alleles, 1 homozygote) in the European (non-Finnish) population. This variant has been reported as a hypomorphic allele with a milder macula-predominant retinal phenotype. It has been detected in at least 18 individuals with an inherited retinal disorder. Of those individuals, nine individuals were homozygous and seven were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 28765526, 28885867, 29555955, 31387115, 32681094, 33546218). The variant has been reported to segregate with retinal disorders in three families (PMID: 28885867, 31387115, 32681094). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PS3_Supporting, PP3, BS1.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000625429	SCV002507066	uncertain significance	Cone-rod dystrophy 15	2022-05-04	criteria provided, single submitter	curation	The heterozygous p.Pro261= variant in CDHR1 was identified by our study in the compound heterozygous state, along with a pathogenic variant, in 1 individual with cone-rod dystrophy 15. The variant has been reported in at least 7 individuals of European and unknown ethnicity with cone-rod dystrophy 15 (PMID: 23591405, 28885867, 28765526), and has been identified in 0.5891 (148/25122) of European Finnish chromosomes and 4 homozygotes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs147346345). This variant has also been reported in ClinVar (Variation ID: 301224) as having uncertain significance by many submitters, as likely pathogenic by Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet, as pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, and as benign by Invitae. In vitro functional studies provide some evidence that the p.Pro261= variant may slightly impact protein function (PMID: 28765526). However, these types of assays may not accurately represent biological function. This variant is located in the last three bases of the exon, which is part of the 3’ splice region. Computational tools suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. The presence of this variant in 3 affected homozygotes, in combination with reported pathogenic and likely pathogenic variants, and in at least 7 individuals with cone-rod dystrophy 15 increases the likelihood that the p.Pro261= variant is pathogenic (Variation ID: 18416; PMID: 28885867). In summary, the clinical significance of the p.Pro261= variant is uncertain. ACMG/AMP Criteria applied: BS1, PM3_strong, PP3, PS3_supporting (Richards 2015).
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787811	SCV000926821	likely pathogenic	Retinal dystrophy	2018-04-01	no assertion criteria provided	research
OMIM	RCV003221896	SCV003852632	pathogenic	Macular dystrophy, retinal, 5	2014-01-01	no assertion criteria provided	literature only
OMIM	RCV003221895	SCV003852633	pathogenic	Retinitis pigmentosa 65	2014-01-01	no assertion criteria provided	literature only
OMIM	RCV000625429	SCV003852634	pathogenic	Cone-rod dystrophy 15	2014-01-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748711	SCV005353534	uncertain significance	CDHR1-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The CDHR1 c.783G>A variant is not predicted to result in an amino acid change (p.=). This variant has been reported in either a homozygous state or along with a second causative variant in multiple families with retinal disorders (Charbel Issa et al. 2019. Pubmed ID: 31387115; Glöckle et al. 2014. PubMed ID: 23591405; Stingl et al. 2017. PubMed ID: 28765526; Tiwari et al. 2016. PubMed ID: 27353947). This substitution affects the last nucleotide of exon 8 and may affect normal exon splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). cDNA analysis demonstrated that this variant results in in-frame exon skipping (Charbel Issa et al. 2019. PubMed ID: 31387115). This variant is registered in the ClinVar database with conflicting interpretations of pathogenicity from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/301224/). This variant is reported in 0.59% of alleles in individuals of European (Finnish) descent in gnomAD including four homozygotes. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.