ClinVar Genomic variation as it relates to human health
NM_033100.4(CDHR1):c.783G>A (p.Pro261=)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Likely pathogenic(6); Uncertain significance(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_033100.4(CDHR1):c.783G>A (p.Pro261=)
Variation ID: 301224 Accession: VCV000301224.64
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.1 10: 84203123 (GRCh38) [ NCBI UCSC ] 10: 85962879 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033100.4:c.783G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_149091.1:p.Pro261= synonymous NM_001171971.3:c.783G>A NP_001165442.1:p.Pro261= synonymous NC_000010.11:g.84203123G>A NC_000010.10:g.85962879G>A NG_028034.1:g.13468G>A - Protein change
- Other names
- NM_033100.4(CDHR1):c.783G>A
- p.Pro261=
- Canonical SPDI
- NC_000010.11:84203122:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- exon loss Variation Ontology [VariO:0381]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00100 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00170
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00231
The Genome Aggregation Database (gnomAD) 0.00446
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CDHR1 | - | - |
GRCh38 GRCh37 |
895 | 946 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, single submitter
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Feb 14, 2019 | RCV000787811.10 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000487554.45 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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May 4, 2022 | RCV000625429.25 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000369498.13 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2014 | RCV003221896.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 19, 2018 | RCV000825304.14 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2014 | RCV003221895.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2021 | RCV001723886.11 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950224.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 15
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002072635.2
First in ClinVar: Feb 05, 2022 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(May 04, 2022)
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criteria provided, single submitter
Method: curation
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Cone-rod dystrophy 15
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV002507066.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
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 … (more)
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). (less)
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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cone-Rod Dystrophy, Recessive
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000365411.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Oct 27, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000701570.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Dec 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966599.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Oct 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617830.3
First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023 |
Comment:
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 … (more)
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 suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in apparent homozygous state in multiple unrelated individuals in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23591405, 28885867, 28224992, 28765526, 30718709, 34426522, 31387115, 34795310, 32681094, 35836572, 32037395, 29555955, 34327195, 32531858) (less)
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Likely pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001038155.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000574853.26
First in ClinVar: May 08, 2017 Last updated: Apr 15, 2024 |
Comment:
CDHR1: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3, PS3:Supporting
Number of individuals with the variant: 23
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 15
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138101.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
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Uncertain significance
(Feb 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001238981.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446677.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Macular dystrophy (present)
Sex: male
|
|
Likely pathogenic
(Dec 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 15
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370120.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
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.
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Uncertain significance
(Dec 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159162.2
First in ClinVar: Feb 09, 2020 Last updated: Jan 26, 2021 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jan 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 15
Affected status: yes
Allele origin:
unknown
|
Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548024.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: WES
|
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Likely pathogenic
(Dec 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy 15
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440752.3
First in ClinVar: Oct 31, 2020 Last updated: Jan 01, 2022 |
Comment:
This variant was identified as homozygous._x000D_ Criteria applied: PS3, PS4_MOD, PM3_SUP
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Pathogenic
(Jan 01, 2014)
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no assertion criteria provided
Method: literature only
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MACULAR DYSTROPHY, RETINAL, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV003852632.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment on evidence:
In 2 patients with retinal dystrophies, Stingl et al. (2017) identified an exonic splice site mutation in the CDHR1 gene, a c.783G-A transition (c.783G-A, NM_033100) … (more)
In 2 patients with retinal dystrophies, Stingl et al. (2017) identified an exonic splice site mutation in the CDHR1 gene, a c.783G-A transition (c.783G-A, NM_033100) in the last nucleotide of exon 8 predicted to result in a synonymous substitution, pro261-to-pro (P261P). However, RT-PCR of transfected HEK293T cells demonstrated that the c.783G-A variant causes skipping of exon 8, and pyrosequencing-based allele quantification revealed markedly reduced expression of the mutant CDHR1 allele. The first patient was a 61-year-old woman (patient H) with primarily macular changes (MCDR5; see 613660) who was homozygous for the c.783G-A variant. The second patient was a 71-year-old man (patient G) with retinitis pigmentosa (RP65; see 613660), originally reported by Glockle et al. (2014) as patient 924, who was compound heterozygous for the c.783G-A variant and a 6-bp deletion (c.1311_1316del; 609502.0006), predicted to result in the in-frame deletion of 2 well-conserved amino acids (Leu437_Thr438del) in the fourth cadherin repeat. Parental DNA status was not reported. The c.783G-A variant was found at a minor allele frequency of 0.34% in the ExAC database, whereas the deletion was not found in ExAC. Both patients exhibited mild disease, and the authors concluded that c.783G-A represents a hypomorphic allele associated with reduced levels of CDHR1 transcripts that may be unmasked as being deleterious when present in the homozygous state or in heterozygous state with another pathogenic allele. In a retrospective case series of patients presenting with retinal dystrophy, Bessette et al. (2018) identified 4 patients who were homozygous or compound heterozygous for the c.783G-A mutation in the CDHR1 gene. The variant was found in homozygosity in 2 patients with RP (cases 1 and 2), who presented with night blindness and constricted visual fields, and showed pale optic nerves, arteriolar attenuation, and bone-spicule pigmentation in the midperipheral retina on funduscopy. Two sisters (cases 3 and 4) with a milder phenotype were compound heterozygous for the c.783G-A change and a splice site variant (c.152-2A-G). Segregation analysis and functional studies were not reported. The authors suggested that homozygosity for the c.783G-A variant might be associated with a more severe phenotype. Charbel Issa et al. (2019) reported 6 patients from 5 families (group 1, patients 1.1 to 1.6) with slowly progressive macular atrophy who were homozygous for the c.783G-A transition in the CDHR1 gene, which segregated with disease in the families for which relatives' DNA was available. Functional analysis using patient whole blood RNA demonstrated aberrant splicing with in-frame skipping of exon 8. Noting that the variant was present in the gnomAD database at a relatively high minor allele frequency (0.31%), with 5 homozygotes, the authors suggested that the relatively mild and late-onset phenotype might mean that those individuals were in the presymptomatic stage of disease, or that there is incomplete penetrance of c.783G-A homozygosity, or that modifiers contribute to the phenotype. The authors also identified 4 patients with CORD phenotypes, 2 of whom (group 2, patients 2.1 and 2.2) were compound heterozygous for the c.783G-A variant and truncating mutations in CDHR1, and 2 of whom (group 3, patients 3.1 and 3.2) were homozygous or compound heterozygous for truncating mutations in CDHR1. The authors concluded that c.783G-A represents a mild hypomorphic mutation, resulting in disease essentially restricted to the macula, whereas biallelic truncating mutations lead to retina-wide cone-rod dystrophy with severe function loss. Noting that homozygosity for the c.783G-A variant previously had been reported in patients with a diagnosis of RP, the authors stated that the reason for the considerable phenotypic difference remained unclear. Ba-Abbad et al. (2021) reviewed the clinical records of patients with macular dystrophy and biallelic variants in the CDHR1 gene, and identified 1 woman (family GC24117) who was homozygous for the c.783G-A variant, as well as 5 more patients from 4 families (GC17748, GC26788, GC20637, and GC27924) who were compound heterozygous for c.783G-A and another mutation in CDHR1. In 4 patients with retinal dystrophies, Malechka et al. (2022) identified compound heterozygosity for the c.783G-A variant and another mutation in the CDHR1 gene: in 2 Greek women, one diagnosed with rod-cone dystrophy and the other with late-onset macular degeneration, the second mutation was a 7-bp deletion (c.2522_2528delTCTCTGA; 609502.0010), causing a frameshift predicted to result in a premature termination codon (Ile841SerfsTer119). The remaining 2 patients were a woman with rod-cone dystrophy, in whom the second mutation was a 7.38-Mb deletion that included the CDHR1 gene, and in a Romanian man with cone-rod disease, in whom the second mutation was a nonsense mutation (Y509X). (less)
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Pathogenic
(Jan 01, 2014)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 65
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV003852633.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment on evidence:
In 2 patients with retinal dystrophies, Stingl et al. (2017) identified an exonic splice site mutation in the CDHR1 gene, a c.783G-A transition (c.783G-A, NM_033100) … (more)
In 2 patients with retinal dystrophies, Stingl et al. (2017) identified an exonic splice site mutation in the CDHR1 gene, a c.783G-A transition (c.783G-A, NM_033100) in the last nucleotide of exon 8 predicted to result in a synonymous substitution, pro261-to-pro (P261P). However, RT-PCR of transfected HEK293T cells demonstrated that the c.783G-A variant causes skipping of exon 8, and pyrosequencing-based allele quantification revealed markedly reduced expression of the mutant CDHR1 allele. The first patient was a 61-year-old woman (patient H) with primarily macular changes (MCDR5; see 613660) who was homozygous for the c.783G-A variant. The second patient was a 71-year-old man (patient G) with retinitis pigmentosa (RP65; see 613660), originally reported by Glockle et al. (2014) as patient 924, who was compound heterozygous for the c.783G-A variant and a 6-bp deletion (c.1311_1316del; 609502.0006), predicted to result in the in-frame deletion of 2 well-conserved amino acids (Leu437_Thr438del) in the fourth cadherin repeat. Parental DNA status was not reported. The c.783G-A variant was found at a minor allele frequency of 0.34% in the ExAC database, whereas the deletion was not found in ExAC. Both patients exhibited mild disease, and the authors concluded that c.783G-A represents a hypomorphic allele associated with reduced levels of CDHR1 transcripts that may be unmasked as being deleterious when present in the homozygous state or in heterozygous state with another pathogenic allele. In a retrospective case series of patients presenting with retinal dystrophy, Bessette et al. (2018) identified 4 patients who were homozygous or compound heterozygous for the c.783G-A mutation in the CDHR1 gene. The variant was found in homozygosity in 2 patients with RP (cases 1 and 2), who presented with night blindness and constricted visual fields, and showed pale optic nerves, arteriolar attenuation, and bone-spicule pigmentation in the midperipheral retina on funduscopy. Two sisters (cases 3 and 4) with a milder phenotype were compound heterozygous for the c.783G-A change and a splice site variant (c.152-2A-G). Segregation analysis and functional studies were not reported. The authors suggested that homozygosity for the c.783G-A variant might be associated with a more severe phenotype. Charbel Issa et al. (2019) reported 6 patients from 5 families (group 1, patients 1.1 to 1.6) with slowly progressive macular atrophy who were homozygous for the c.783G-A transition in the CDHR1 gene, which segregated with disease in the families for which relatives' DNA was available. Functional analysis using patient whole blood RNA demonstrated aberrant splicing with in-frame skipping of exon 8. Noting that the variant was present in the gnomAD database at a relatively high minor allele frequency (0.31%), with 5 homozygotes, the authors suggested that the relatively mild and late-onset phenotype might mean that those individuals were in the presymptomatic stage of disease, or that there is incomplete penetrance of c.783G-A homozygosity, or that modifiers contribute to the phenotype. The authors also identified 4 patients with CORD phenotypes, 2 of whom (group 2, patients 2.1 and 2.2) were compound heterozygous for the c.783G-A variant and truncating mutations in CDHR1, and 2 of whom (group 3, patients 3.1 and 3.2) were homozygous or compound heterozygous for truncating mutations in CDHR1. The authors concluded that c.783G-A represents a mild hypomorphic mutation, resulting in disease essentially restricted to the macula, whereas biallelic truncating mutations lead to retina-wide cone-rod dystrophy with severe function loss. Noting that homozygosity for the c.783G-A variant previously had been reported in patients with a diagnosis of RP, the authors stated that the reason for the considerable phenotypic difference remained unclear. Ba-Abbad et al. (2021) reviewed the clinical records of patients with macular dystrophy and biallelic variants in the CDHR1 gene, and identified 1 woman (family GC24117) who was homozygous for the c.783G-A variant, as well as 5 more patients from 4 families (GC17748, GC26788, GC20637, and GC27924) who were compound heterozygous for c.783G-A and another mutation in CDHR1. In 4 patients with retinal dystrophies, Malechka et al. (2022) identified compound heterozygosity for the c.783G-A variant and another mutation in the CDHR1 gene: in 2 Greek women, one diagnosed with rod-cone dystrophy and the other with late-onset macular degeneration, the second mutation was a 7-bp deletion (c.2522_2528delTCTCTGA; 609502.0010), causing a frameshift predicted to result in a premature termination codon (Ile841SerfsTer119). The remaining 2 patients were a woman with rod-cone dystrophy, in whom the second mutation was a 7.38-Mb deletion that included the CDHR1 gene, and in a Romanian man with cone-rod disease, in whom the second mutation was a nonsense mutation (Y509X). (less)
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Pathogenic
(Jan 01, 2014)
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no assertion criteria provided
Method: literature only
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CONE-ROD DYSTROPHY 15
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV003852634.1
First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023 |
Comment on evidence:
In 2 patients with retinal dystrophies, Stingl et al. (2017) identified an exonic splice site mutation in the CDHR1 gene, a c.783G-A transition (c.783G-A, NM_033100) … (more)
In 2 patients with retinal dystrophies, Stingl et al. (2017) identified an exonic splice site mutation in the CDHR1 gene, a c.783G-A transition (c.783G-A, NM_033100) in the last nucleotide of exon 8 predicted to result in a synonymous substitution, pro261-to-pro (P261P). However, RT-PCR of transfected HEK293T cells demonstrated that the c.783G-A variant causes skipping of exon 8, and pyrosequencing-based allele quantification revealed markedly reduced expression of the mutant CDHR1 allele. The first patient was a 61-year-old woman (patient H) with primarily macular changes (MCDR5; see 613660) who was homozygous for the c.783G-A variant. The second patient was a 71-year-old man (patient G) with retinitis pigmentosa (RP65; see 613660), originally reported by Glockle et al. (2014) as patient 924, who was compound heterozygous for the c.783G-A variant and a 6-bp deletion (c.1311_1316del; 609502.0006), predicted to result in the in-frame deletion of 2 well-conserved amino acids (Leu437_Thr438del) in the fourth cadherin repeat. Parental DNA status was not reported. The c.783G-A variant was found at a minor allele frequency of 0.34% in the ExAC database, whereas the deletion was not found in ExAC. Both patients exhibited mild disease, and the authors concluded that c.783G-A represents a hypomorphic allele associated with reduced levels of CDHR1 transcripts that may be unmasked as being deleterious when present in the homozygous state or in heterozygous state with another pathogenic allele. In a retrospective case series of patients presenting with retinal dystrophy, Bessette et al. (2018) identified 4 patients who were homozygous or compound heterozygous for the c.783G-A mutation in the CDHR1 gene. The variant was found in homozygosity in 2 patients with RP (cases 1 and 2), who presented with night blindness and constricted visual fields, and showed pale optic nerves, arteriolar attenuation, and bone-spicule pigmentation in the midperipheral retina on funduscopy. Two sisters (cases 3 and 4) with a milder phenotype were compound heterozygous for the c.783G-A change and a splice site variant (c.152-2A-G). Segregation analysis and functional studies were not reported. The authors suggested that homozygosity for the c.783G-A variant might be associated with a more severe phenotype. Charbel Issa et al. (2019) reported 6 patients from 5 families (group 1, patients 1.1 to 1.6) with slowly progressive macular atrophy who were homozygous for the c.783G-A transition in the CDHR1 gene, which segregated with disease in the families for which relatives' DNA was available. Functional analysis using patient whole blood RNA demonstrated aberrant splicing with in-frame skipping of exon 8. Noting that the variant was present in the gnomAD database at a relatively high minor allele frequency (0.31%), with 5 homozygotes, the authors suggested that the relatively mild and late-onset phenotype might mean that those individuals were in the presymptomatic stage of disease, or that there is incomplete penetrance of c.783G-A homozygosity, or that modifiers contribute to the phenotype. The authors also identified 4 patients with CORD phenotypes, 2 of whom (group 2, patients 2.1 and 2.2) were compound heterozygous for the c.783G-A variant and truncating mutations in CDHR1, and 2 of whom (group 3, patients 3.1 and 3.2) were homozygous or compound heterozygous for truncating mutations in CDHR1. The authors concluded that c.783G-A represents a mild hypomorphic mutation, resulting in disease essentially restricted to the macula, whereas biallelic truncating mutations lead to retina-wide cone-rod dystrophy with severe function loss. Noting that homozygosity for the c.783G-A variant previously had been reported in patients with a diagnosis of RP, the authors stated that the reason for the considerable phenotypic difference remained unclear. Ba-Abbad et al. (2021) reviewed the clinical records of patients with macular dystrophy and biallelic variants in the CDHR1 gene, and identified 1 woman (family GC24117) who was homozygous for the c.783G-A variant, as well as 5 more patients from 4 families (GC17748, GC26788, GC20637, and GC27924) who were compound heterozygous for c.783G-A and another mutation in CDHR1. In 4 patients with retinal dystrophies, Malechka et al. (2022) identified compound heterozygosity for the c.783G-A variant and another mutation in the CDHR1 gene: in 2 Greek women, one diagnosed with rod-cone dystrophy and the other with late-onset macular degeneration, the second mutation was a 7-bp deletion (c.2522_2528delTCTCTGA; 609502.0010), causing a frameshift predicted to result in a premature termination codon (Ile841SerfsTer119). The remaining 2 patients were a woman with rod-cone dystrophy, in whom the second mutation was a 7.38-Mb deletion that included the CDHR1 gene, and in a Romanian man with cone-rod disease, in whom the second mutation was a nonsense mutation (Y509X). (less)
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Likely pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926821.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Clinical Phenotypes of CDHR1-Associated Retinal Dystrophies. | Malechka VV | Genes | 2022 | PMID: 35627310 |
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases. | Fadaie Z | NPJ genomic medicine | 2021 | PMID: 34795310 |
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
A clinical study of patients with novel CDHR1 genotypes associated with late-onset macular dystrophy. | Ba-Abbad R | Eye (London, England) | 2021 | PMID: 32681094 |
A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a Silent Mutation Leading to In-Frame Exon Skipping. | Charbel Issa P | Investigative ophthalmology & visual science | 2019 | PMID: 31387115 |
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. | Birtel J | Scientific reports | 2018 | PMID: 29555955 |
Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene and a review of the literature. | Bessette AP | Ophthalmic genetics | 2018 | PMID: 28885867 |
CDHR1 mutations in retinal dystrophies. | Stingl K | Scientific reports | 2017 | PMID: 28765526 |
Diagnostic exome sequencing in 266 Dutch patients with visual impairment. | Haer-Wigman L | European journal of human genetics : EJHG | 2017 | PMID: 28224992 |
Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies. | Tiwari A | Scientific reports | 2016 | PMID: 27353947 |
Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. | Glöckle N | European journal of human genetics : EJHG | 2014 | PMID: 23591405 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CDHR1 | - | - | - | - |
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Text-mined citations for rs147346345 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.