chr10-84214556-ACTCTGAT-A

Variant names:

• chr10-84214556-ACTCTGAT-A
• rs794727197
• NM_033100.4:c.2522_2528delTCTCTGA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_033100.4(CDHR1):​c.2522_2528delTCTCTGA​(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

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 0.0225 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 rank	MANE	Protein	UniProt
CDHR1	NM_033100.4	c.2522_2528delTCTCTGA	p.Ile841SerfsTer119	frameshift_variant	Exon 17 of 17	ENST00000623527.4	NP_149091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR1	ENST00000623527.4	c.2522_2528delTCTCTGA	p.Ile841SerfsTer119	frameshift_variant	Exon 17 of 17	1	NM_033100.4	ENSP00000485478.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152024 Hom.: 0 Cov.: 33

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: 8 AN: 241492 Hom.: 0 AF XY: 0.0000381 AC XY: 5 AN XY: 131360

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: 21 AN: 1449064 Hom.: 0 AF XY: 0.0000139 AC XY: 10 AN XY: 721390

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: 3 AN: 152024 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74254

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:14 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 20, 2014

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 37510321, 35260635, 31964843, 36460718, 33749171, 37734845, 27623334, 28041643, 29555955, 31387115, 31130284, 32581362, 28765526, 35656873, 26766544, 33576794, 30718709, 35836572, 34229535) -

Cone-rod dystrophy 15 Pathogenic:4

Feb 21, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -

Jan 20, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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’s 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). -

Retinal dystrophy Pathogenic:2

Jul 03, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:2

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinitis pigmentosa 65 Pathogenic:1

Mar 30, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Macular dystrophy, retinal, 5 Pathogenic:1

Mar 30, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cone dystrophy Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794727197; hg19: chr10-85974312;