Submissions for variant NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu)

gnomAD frequency: 0.00001  dbSNP: rs397517349

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000758142	SCV000886634	uncertain significance	Usher syndrome	2023-11-15	reviewed by expert panel	curation	The variant c.6614C>T (NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu)) in CDH23 is a missense variant predicted to cause substitution of proline by leucine at amino acid 2205 (p.Pro2205Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000002920 (8/1179896 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.342, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function. This variant has been detected in at least 8 individuals with autosomal recessive hearing loss. All of these individuals were homozygous for the variant (1.0 pts; PMIDs: 28501645, 32747562 & LMM Internal Data (SCV000062934.5); PM3). There was a common haplotype found between five affected individuals from three families, one of which had three affected siblings, including a set of twins. Personal communication confirmed the three siblings were sequenced; however, it was not apparent whether the twins were dizygotic or monozygotic and therefore only one twin was counted toward segregation (PP1_Supporting; 28501645). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PM3, PP1_Supporting; Version 2; 11/15/23).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017328	SCV000062934	uncertain significance	Rare genetic deafness	2023-02-02	criteria provided, single submitter	clinical testing	The p.Pro2205Leu variant in CDH23 has been reported in 3 individuals with hearing loss and 1 individual with Usher syndrome, 3 of whom were of Middle Eastern ancestry (Syrian, Saudi Arabian, Kuwaiti; Sloan-Heggen 2016, LMM data). Of the three individuals with hearing loss, one was homozygous, one individual was heterozygous, and one was compound heterozygous with a second CDH23 variant of uncertain significance. The individual with Usher syndrome was homozygous for a pathogenic variant in another gene that could account for the disease. This variant was absent from large population studies, though none of these studies specify frequency data for individuals of Middle Eastern ancestry. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting.
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171176	SCV000221373	likely pathogenic	not provided		criteria provided, single submitter	research
Ambry Genetics	RCV000210550	SCV000263017	uncertain significance	Inborn genetic diseases		criteria provided, single submitter	clinical testing	Overall WES conclusion for patient, including all identified alterations: Uncertain
GeneDx	RCV000171176	SCV000569425	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	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: 25356970, 34426522, 31860473, 34338889, 32747562, 26969326, 28501645)
Baylor Genetics	RCV001331233	SCV001523227	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2019-08-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
King Laboratory, University of Washington	RCV001331233	SCV002059908	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 12	2020-08-01	criteria provided, single submitter	research	CDH23 c.6614C>T, p.E1071K alters a highly conserved residue of CDH23. The variant is homozygous in 3 children from 2 Palestinian families with moderate pre-lingual hearing loss (Abu Rayyan 2020). It was found also in 6 Palestinian children in compound heterozygosity with CDH23 c.1675C>T. The variant is absent from 1300 Palestinian controls and from gnomAD v2.1.1. This variant was previously interpreted as a VUS by the Expert Panel due to few Arab population controls. We suggest reclassification to LP given perfect co-segregation with hearing loss in additional families (both as a homozygote and as a compound heterozygote) and its absence from 1300 ancestry-matched controls
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000758142	SCV002074447	pathogenic	Usher syndrome	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.6614C>T (p.Pro2205Leu) results in a non-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 4e-06 in 248748 control chromosomes (gnomAD v2), absent in 316 control individuals from Middle Eastern (gnomAD v3) and absent in 1309 Palestinian controls (Rayyan _2020). c.6614C>T has been reported in the literature in multiple individuals affected with Non-syndromic hearing loss, including being seen phase unknown along with a VUS missense in a sporadic case (Sloan_Heggen_2016), in homozygous state in 5 patients from 3 consanguineous pedigrees in Qatar (Alkowari_2017), and in homozygous state in 2 patients from 2 Palestinian families (Rayyan _2020). Haplotype analysis of the patients revealed a same haplotype across those patients from Qatar, which support a common ancestor in those patients or a founder effect of this variant (Alkowari_2017). 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: 28501645, 29048421, 32747562, 26969326). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 among which four (including the ClinGen Hearing Loss Variant Curation Expert Panel) classified the variant as VUS, and one as likely pathogenic. Some submitters classifying the variant as uncertain significance cited the expert panel assertion and cited overlapping but not identical evidence captured in the context of this ascertainment. Based on the additional emerging evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003152590	SCV003841213	likely pathogenic	Usher syndrome type 1D		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473282	SCV004210590	likely pathogenic	Pituitary adenoma 5, multiple types	2023-10-22	criteria provided, single submitter	clinical testing