CDHR1

protein-coding

cadherin related family member 1, the group of Cadherin related

Gene summary

This gene belongs to the cadherin superfamily of calcium-dependent cell adhesion molecules. The encoded protein is a photoreceptor-specific cadherin that plays a role in outer segment disc morphogenesis. Mutations in this gene are associated with inherited retinal dystrophies. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2013]

Previous symbols:

PCDH21

MANE transcript

NM_033100.4

Inheritance

AR, AD

ClinVar variants

P:117U:455B:235

Top phenotype

Cone-rod dystrophy 15; Retinitis pigmentosa 65

gnomAD constraint

pLI —, LoF o/e 0.98

Max pathogenic AF

—

Genomic locus

chr10:84,194,537-84,219,621

External References & Databases

Ensembl (ENSG00000148600)

Transcript & Mutation Effects

hg38 • Region Span ~25.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa 65DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800352

Submitter: ClinGen

The *CDHR1 *gene was first reported in relation to autosomal recessive cone-rod dystrophy (PMID 20463681), and retinal degeneration (PMID 20463681) in 2010. *CDHR1*-related retinopathy can manifest in various but progressive forms of retinal degeneration, including cone-rod dystrophy, rod-cone dystrophy, and late-onset macular degeneration (LOMD) (PMID 30060493). The onset of clinical symptoms of *CDHR1*-related retinopathy may span a wide range (5-45 years). Clinically, patients exhibit reduced visual acuity, color vision defects, photophobia, nyctalopia, visual field defects (constricted VF or central scotoma), and ERG defects (PMID 23379534). Interestingly, one relatively common synonymous variant, c.783G>A, resulting in skipping of exon 8 and leading to the in-frame deletion of 48 amino acids of the CDHR1 ectodomain, has been frequently reported as a hypomorphic variant causing late-onset macular dystrophy (PMIDs 30060493, 23379534). In a recent study, the c.783G>A variant was also noted to confer incomplete penetrance (PMID 30060493). Five variants (missense, synonymous, and pLOF) that have been reported in five publications (PMIDs 20463681, 23379534, 30060493, 20463681, 23379534) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. There are 99 pathogenic or likely pathogenic *CDHR1* variants listed on ClinVar (PMID 23379534). The mechanism of pathogenicity is reported to be loss of function (LOF). This gene-disease relationship is also supported by functional studies in mice, where homozygous Cdhr1 knock-out mice showed progressive outer retinal degeneration (PMID 20463681). In summary, CDHR1 is definitively associated with autosomal recessive retinopathy. This has been repeatedly demonstrated in research and clinical diagnostic settings and has been upheld over time.

cone-rod dystrophy 15DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013348

Submitter: Ambry Genetics

cone-rod dystrophy 15DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013348

Submitter: G2P

cone-rod dystrophy 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013348

Submitter: Labcorp Genetics (formerly Invitae)

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cone-rod dystrophy 15; Retinitis pigmentosa 65AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 20805371

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDHR1 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 876

Inborn genetic diseasesTotal: 137

not specifiedTotal: 115

Cone-rod dystrophy 15Total: 111

CDHR1-related disorderTotal: 94

CDHR1-related disordersTotal: 48

Retinal dystrophyTotal: 38

Retinitis pigmentosaTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033100.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	6 clinvar	185 clinvar		192
missense	1 clinvar	8 clinvar	441 clinvar	48 clinvar	2 clinvar	500
nonsense	15 clinvar	7 clinvar	2 clinvar			24
start loss	2 clinvar					2
frameshift	31 clinvar	18 clinvar	5 clinvar			54
splice donor/acceptor (+/-2bp)	9 clinvar	25 clinvar	1 clinvar			35
Total	58	59	455	233	2	807

Highest pathogenic variant AF is 0.002367146

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033100.4	RefSeq	NP_149091.1	17	MANE Select
ENST00000623527.4	Ensembl	ENSP00000485478.1	17	MANE Select
NM_001171971.3	RefSeq	NP_001165442.1	17	Standard
ENST00000332904.7	Ensembl	ENSP00000331063.3	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cell adhesion
homophilic cell adhesion via plasma membrane adhesion molecules
photoreceptor cell morphogenesis
photoreceptor cell outer segment organization
photoreceptor cell maintenance

Molecular Function

molecular_function
calcium ion binding

Cellular Component

cellular_component
integral component of plasma membrane
photoreceptor outer segment membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372117
Coding exons: 17
Length: 24968
Individuals with no LoFs: 125652
Homozygous LoFs: 0
Heterozygous LoFs: 96
Defined: 125748
p: 0.000382

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.697	534	491	1.09	0.0000305	5605
Missense (PolyPhen)		165	155.58	1.0606		1777
Synonymous	-0.229	210	206	1.02	0.0000145	1769
Loss of Function	0.126	32	32.8	0.976	0.00000160	392

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00057	0.00055	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00069	0.00069	rare
Other	0.00081	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potential calcium-dependent cell-adhesion protein. May be required for the structural integrity of the outer segment (OS) of photoreceptor cells (By similarity). {ECO:0000250}.;
Disease: DISEASE: Cone-rod dystrophy 15 (CORD15) [MIM:613660]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:20805371, ECO:0000269|PubMed:26350383}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.144

Intolerance Scores

LoFtool: 0.893
RVIS EVS: 0.01
RVIS percentile EVS: 54.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium