Submissions for variant NM_033100.4(CDHR1):c.2522_2528del (p.Ile841fs)

dbSNP: rs794727197

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000262674	SCV000331654	likely pathogenic	not provided	2014-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000262674	SCV001202193	pathogenic	not provided	2024-06-22	criteria provided, single submitter	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.
Blueprint Genetics	RCV001075783	SCV001241416	pathogenic	Retinal dystrophy	2019-07-03	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199122	SCV001370117	pathogenic	Cone-rod dystrophy 15	2019-02-21	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000262674	SCV001447607	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV001199122	SCV001548115	likely pathogenic	Cone-rod dystrophy 15	2021-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000262674	SCV001987753	pathogenic	not provided	2023-09-06	criteria provided, single submitter	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)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001199122	SCV002072558	likely pathogenic	Cone-rod dystrophy 15	2022-01-20	criteria provided, single submitter	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
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001199122	SCV003761294	pathogenic	Cone-rod dystrophy 15	2023-01-25	criteria provided, single submitter	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).
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075783	SCV005072335	likely pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504886	SCV000599036	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626977	SCV000747680	uncertain significance	Cone dystrophy	2017-01-01	flagged submission	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504886	SCV000926533	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
OMIM	RCV003221834	SCV003852639	pathogenic	Retinitis pigmentosa 65	2023-03-30	no assertion criteria provided	literature only
OMIM	RCV003221835	SCV003852640	pathogenic	Macular dystrophy, retinal, 5	2023-03-30	no assertion criteria provided	literature only