Variant rs794727197 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_033100.4(CDHR1):c.2522_2528del(p.Ile841SerfsTer119) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,601,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CDHR1
NM_033100.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:2

Conservation

PhyloP100: 7.67

Variant links:

Genes affected

CDHR1 (HGNC:14550): (cadherin related family member 1) 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]

CDHR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0248 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-84214556-ACTCTGAT-A is Pathogenic according to our data. Variant chr10-84214556-ACTCTGAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 194793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-84214556-ACTCTGAT-A is described in Lovd as [Pathogenic]. Variant chr10-84214556-ACTCTGAT-A is described in Lovd as [Likely_pathogenic]. Variant chr10-84214556-ACTCTGAT-A is described in Lovd as [Likely_pathogenic]. Variant chr10-84214556-ACTCTGAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDHR1	NM_033100.4 linkuse as main transcript	c.2522_2528del	p.Ile841SerfsTer119	frameshift_variant	17/17	ENST00000623527.4	NP_149091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDHR1	ENST00000623527.4 linkuse as main transcript	c.2522_2528del	p.Ile841SerfsTer119	frameshift_variant	17/17	1	NM_033100.4	ENSP00000485478	P2	Q96JP9-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000331

AC:

AN:

241492

Hom.:

AF XY:

0.0000381

AC XY:

AN XY:

131360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000145

AC:

AN:

1449064

Hom.:

AF XY:

0.0000139

AC XY:

AN XY:

721390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cone-rod dystrophy 15

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 20, 2022	This variant was identified as homozygous. Another variante (NM_002921.4:c.196A>C) was found in the same patient. Criteria applied: PVS1_MOD, PS4_MOD, PM3, PM2_SUP -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 21, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Ile841SerfsTer119 variant in CDHR1 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (Variation ID: 1213967), in one individual with cone-rod dystrophy. This individual also carried a likely pathogenic variant (ClinVar Variation ID: 1213967); however, the phase of these variants is unknown at this time. The p.Ile841SerfsTer119 variant in CDHR1 has been previously reported in 12 unrelated individuals with autosomal recessive cone-rod dystrophy 15 (PMID: 28765526, PMID: 31130284, PMID: 32581362, PMID: 30718709, PMID: 31387115, PMID: 29555955, PMID: 28041643, PMID: 26766544) and segregated with disease in 5 affected relatives from two families (PMID: 28765526), but has been identified in 0.006% (7/113220) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1429453310). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 12 previously reported affected individuals (PMID: 28765526, PMID: 31130284, PMID: 32581362, PMID: 30718709, PMID: 31387115, PMID: 29555955, PMID: 28041643, PMID: 26766544), 6 were homozygotes (PMID: 32581362, PMID: 28765526, PMID: 28041643), 2 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 31130284, ClinVar Variation ID: 812262; PMID: 32581362, ClinVar Variation ID: 438117) and 4 were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 26766544, PMID: 28765526, ClinVar Variation ID: 438115; PMID: 31387115, PMID: 29555955, ClinVar Variation ID: 301224), which increases the likelihood that the p.Ile841SerfsTer119 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 194793) and has conflicting interpretations of pathogenicity. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 841 and leads to a premature termination codon 119 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the CDHR1 gene is an established disease mechanism in autosomal recessive cone-rod dystrophy 15. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cone-rod dystrophy 15. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting, PM3_VeryStrong, PP1 (Richards 2015). -

not provided

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Uncertain significance, flagged submission	clinical testing	GeneDx	Sep 18, 2020	Frameshift variant predicted to result in protein truncation as the last 19 amino acids are replaced with 118 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 28765526, 26766544, 27623334, 28041643, 29555955, 31387115, 30718709, 31130284, 32581362) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change results in a frameshift in the CDHR1 gene (p.Ile841Serfs*119). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the CDHR1 protein and extend the protein by 99 additional amino acid residues. This variant is present in population databases (rs752341696, gnomAD 0.007%). This frameshift has been observed in individuals with cone rod dystrophy and retinitis pigmentosa (PMID: 26766544, 28041643, 28765526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 194793). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -

Retinitis pigmentosa

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Retinitis pigmentosa 65

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 30, 2023

- -

Macular dystrophy, retinal, 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 30, 2023

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 03, 2019

- -

Cone dystrophy

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over