Submissions for variant NM_022124.6(CDH23):c.3016G>A (p.Glu1006Lys)

gnomAD frequency: 0.00001  dbSNP: rs745571683

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755910	SCV000883560	likely pathogenic	not provided	2018-05-25	criteria provided, single submitter	clinical testing	The p.Glu1006Lys variant (rs745571683) was first reported in patients from a family, where all affected members were bi-allelic for variants in CDH23 with congenital deafness (Schultz 2011). Bi-allelic variants of CDH23 with p.Glu1006Lys was further shown to result in bilateral hearing loss in two siblings who inherited the variants from unaffected parents (Lu 2014). This variant was also reported in the homozygous state in one individual with Usher type I (Aparisi 2014). This variant is listed in the Genome Aggregation Database (gnomAD) identified on 2 chromosomes of 233,072. The glutamic acid at position 1006 is highly conserved up to zebrafish considering 12 species (Alamut v2.11) and computational analyses of the p.Glu1006Lys variant on protein structure and function indicates a deleterious effect (MutationTaster: disease causing, PolyPhen-2: probably damaging). Based on the above, the p.Glu1006Lys variant is considered to be likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825513	SCV000966824	likely pathogenic	Rare genetic deafness	2018-10-26	criteria provided, single submitter	clinical testing	The p.Glu1006Lys variant is CDH23 has been reported in 5 compound heterozygous a nd 1 homozygous individuals with non-syndromic hearing loss or Usher syndrome ty pe I, and segregated with the disease in 1 affected relative (Schultz 2011, Lu 2 014, Aparisi 2014, Zein 2015, Sloan-Heggen 2016). This variant has also been ide ntified in 0.002% (2/105730) of European chromosomes by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org ). Computational prediction to ols and conservation analysis suggest that the p.Glu1006Lys variant may impact t he protein, though this information is not predictive enough to determine pathog enicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu1006Lys variant is likely pathogenic. ACMG/ AMP Criteria applied: PM3_Strong, PM2, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755910	SCV001587034	pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1006 of the CDH23 protein (p.Glu1006Lys). This variant is present in population databases (rs745571683, gnomAD 0.002%). This missense change has been observed in individual(s) with CDH23-related conditions (PMID: 21940737, 25231367, 25404053, 25425308). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 618010). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000755910	SCV001905577	likely pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000755910	SCV002525259	likely pathogenic	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25404053, 25231367, 21940737, 25425308, 26969326, 31589614, 33576794, 33089500)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470968	SCV002766615	pathogenic	Usher syndrome type 1D	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_022124.5(CDH23):c.3016G>A in exon 26 of the CDH23 gene. (NB: this variant is non-coding in alternative transcripts). This substitution is predicted to create a minor amino acid change from a glutamic acid to a lysine at position 1006 of the protein; NP_071407.4(CDH23):p.(Glu1006Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC), and is located at a calcium binding site within the XEX motif of the EC10 domain (Lu, Y. et al. (2014)). In silico software predicts this variant to be damaging (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency of 0.00085% (2 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.0019%. This variant has been previously reported as pathogenic in patients with Usher syndrome or non-syndromic hearing loss (ClinVar). It has also been shown to segregate with disease in two families (Schultz, J. M. et al. (2011), Lu, Y. et al. (2014)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics	RCV002507320	SCV002813664	pathogenic	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2024-02-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003472275	SCV004210625	pathogenic	Pituitary adenoma 5, multiple types	2024-03-25	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003596546	SCV004244560	likely pathogenic	CDH23-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	PM2, PM3_Strong, PP1, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240529	SCV005887776	pathogenic	Usher syndrome	2025-01-13	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.3016G>A (p.Glu1006Lys) 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 8.5e-06 in 235958 control chromosomes. c.3016G>A has been reported in the compound heterozygous or homozygous state in the literature in multiple individuals affected with Usher Syndrome or nonsyndromic deafness (example, Aparisi_2014, Lu_2014, Schultz_2011). 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: 25404053, 25231367, 21940737). ClinVar contains an entry for this variant (Variation ID: 618010). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001271858	SCV001453330	likely pathogenic	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing