chr10-71617295-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_022124.6(CDH23):c.1036C>T(p.Pro346Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P346L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.1036C>T | p.Pro346Ser | missense_variant | 11/70 | ENST00000224721.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.1036C>T | p.Pro346Ser | missense_variant | 11/70 | 5 | NM_022124.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 12 Pathogenic:3
Pathogenic, no assertion criteria provided | research | Hereditary Research Laboratory, Bethlehem University | Jun 04, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Aug 01, 2020 | CDH23 c.1036C>T, p.P346S alters a highly conserved residue of CDH23. The variant is homozygous in 8 children from 3 Palestinian families with pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and from gnomAD v2.1.1. - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center | Jul 01, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | ClinVar contains an entry for this variant (Variation ID: 402250). This missense change has been observed in individual(s) with deafness (PMID: 19888295). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 346 of the CDH23 protein (p.Pro346Ser). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDH23 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro346Leu amino acid residue in CDH23. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19888295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at