ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.6614C>T (p.Pro2205Leu) (rs397517349)

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Total submissions: 5
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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 2018-10-23 reviewed by expert panel curation The p.Pro2205Leu variant in CDH23 gene is absent in gnomAD; however, given poor representation of individuals of Middle Eastern descent, PM2 was not applied. It has been reported in 7 patients with hearing loss: It was found in one sporadic case as a compound heterozygote with another missense change of uncertain significance, but phase was not reported (PMID: 26969326), in a homozygous state in one patient from Middle Eastern background (LMM laboratory: SCV000062934.5) and homozygous in three consanguineous probands from Qatar (PMID:28501645) (PM3_supporting). One of the consanguineous pedigrees (PMID:28501645) had 3 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 and PP1_Supporting was applied. Computational prediction using REVEL did not meet the Hearing Loss Expert Panel (HL EP) specified threshold of >0.7 for PP3. In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive hearing loss based on the HL EP-specified ACMG/AMP criteria applied (PP1_Supporting, PM3_Supporting).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039250 SCV000062934 uncertain significance not specified 2017-04-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro2205Le u variant in CDH23 has been reported in 3 individuals with hearing loss and 1 in dividual 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 la rge population studies, though none of these studies specify frequency data for individuals of Middle Eastern ancestry. Computational prediction tools and con servation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, th e clinical significance of this variant is uncertain.
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 likely pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing The P2205L variant in the CDH23 gene has been reported previously in association with autosomal recessive hearing loss when present in the homozygous state or when heterozygous with another variant (Sloan-Heggen et al., 2016; Alkowari et al., 2017). The P2205L variant is not observed in large population cohorts (Lek et al., 2016). The P2205L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P2205L as a likely pathogenic variant.
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000171176 SCV000221373 likely pathogenic not provided no assertion criteria provided research

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