Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001068516 | SCV001233632 | pathogenic | not provided | 2023-11-19 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 990 of the CDH23 protein (p.Asp990Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with deafness (PMID: 21940737, 29148562, 30303587, 32485727). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 861900). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CDH23 protein function. This variant disrupts the p.Asp990 amino acid residue in CDH23. Other variant(s) that disrupt this residue have been observed in individuals with CDH23-related conditions (PMID: 32645618), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323792 | SCV004029646 | pathogenic | Usher syndrome | 2023-07-25 | criteria provided, single submitter | clinical testing | Variant summary: CDH23 c.2968G>A (p.Asp990Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 228518 control chromosomes, however this information is unreliable due to low quality metrics at this position as indicated by analysis filters incorporated in gnomAD. c.2968G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with non-syndromic hearing loss (e.g., Richard_2019, Schultz_2011, Vanniya_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30303587, 21940737, 29148562). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV003473693 | SCV004212295 | pathogenic | Pituitary adenoma 5, multiple types | 2023-05-20 | criteria provided, single submitter | clinical testing | |
| University of Washington Center for Mendelian Genomics, |
RCV001291209 | SCV001479634 | likely pathogenic | Hearing loss, autosomal recessive | no assertion criteria provided | research | ||
| Natera, |
RCV001827450 | SCV002089956 | likely pathogenic | Usher syndrome type 1 | 2020-07-07 | no assertion criteria provided | clinical testing |