Submissions for variant NM_022124.6(CDH23):c.902G>A (p.Arg301Gln)

gnomAD frequency: 0.00001  dbSNP: rs121908355

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001775064	SCV002011863	uncertain significance	Nonsyndromic genetic hearing loss	2020-11-02	reviewed by expert panel	curation	The allele frequency of the c.902G>A (p.Arg301Gln) variant in the CDH23 gene is 0.0046% (3/64572) of European (non-Finnish) chromosomes by gnomAD v3, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss. This variant was detected in 4 individuals with sensorineural hearing loss with the P240L variant in CDH23. For 2 of these probands the pathogenic P240L variant in CDH23 was present in trans; however, because all the families were of East Asian descent and this variant was always observed with the P240L variant, PM3 was kept at the moderate level (PM3, PMIDs: 17850630, 22443853, 22899989). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (PP3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3.
Eurofins Ntd Llc (ga)	RCV000173892	SCV000225064	uncertain significance	not provided	2016-07-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000173892	SCV001246545	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV000173892	SCV002287033	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 301 of the CDH23 protein (p.Arg301Gln). This variant is present in population databases (rs121908355, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 17850630, 32860223). 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: 4929). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000173892	SCV003805521	likely pathogenic	not provided	2023-02-24	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: 22899989, 22443853, 32860223, 35020051, 35076463, 17850630)
Baylor Genetics	RCV003472979	SCV004210661	pathogenic	Pituitary adenoma 5, multiple types	2023-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478971	SCV004223473	pathogenic	Usher syndrome	2023-11-07	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.902G>A (p.Arg301Gln) results in a conservative amino acid change located in one of the Cadherin-like domains (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249214 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.902G>A has been reported in the literature in multiple individuals affected with non-syndromic hearing loss (e.g., Wagatsuma_2007, Miyagawa_2012, Sloan-Heggen_2016, Safka-Brozkova_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22899989, 32860223, 26969326, 17850630). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic, n = 2; likely pathogenic, n = 1; VUS, n = 2). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000005212	SCV000025390	pathogenic	Autosomal recessive nonsyndromic hearing loss 12	2007-10-01	no assertion criteria provided	literature only