chr10-84214556-ACTCTGAT-A
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_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
Consequence
NM_033100.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152024Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000331 AC: 8AN: 241492Hom.: 0 AF XY: 0.0000381 AC XY: 5AN XY: 131360
GnomAD4 exome AF: 0.0000145 AC: 21AN: 1449064Hom.: 0 AF XY: 0.0000139 AC XY: 10AN XY: 721390
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152024Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74254
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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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) -
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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. -
Cone-rod dystrophy 15 Pathogenic:4
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 -
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -
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
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Retinitis pigmentosa Pathogenic:2
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Retinitis pigmentosa 65 Pathogenic:1
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Macular dystrophy, retinal, 5 Pathogenic:1
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Cone dystrophy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at