ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.9565C>T (p.Arg3189Trp)

gnomAD frequency: 0.00003  dbSNP: rs121908353
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000787978 SCV000927001 uncertain significance Usher syndrome 2022-07-21 reviewed by expert panel curation The c.9565C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 3189. The only evidence resulting in a classification code was determined by the computational predictor REVEL which gives a score of 0.783, which is above the threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00039 (4/10320 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 6/15/2022).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039312 SCV000062996 uncertain significance not specified 2012-05-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg3189Trp vari ant (CDH23) has been reported in the literature twice and was absent from 200 co ntrols (Zheng 2005, Ouyang 2005). However, we suspect that the two reports were not independent and represent the same patient, who may also represent the prese nt patient, based upon the co-occurrence of this variant and the Tyr16fs variant noted in one of the papers. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong supp ort for or against an impact to the protein. In summary, the clinical significan ce of this variant cannot be determined with certainty at this time.
Fulgent Genetics, Fulgent Genetics RCV002482830 SCV002780593 uncertain significance Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types 2022-01-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001358062 SCV003441628 uncertain significance not provided 2022-07-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3189 of the CDH23 protein (p.Arg3189Trp). This variant is present in population databases (rs121908353, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of CDH23-related conditions (PMID: 15537665, 15660226). ClinVar contains an entry for this variant (Variation ID: 4926). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000005209 SCV000025386 pathogenic USHER SYNDROME, TYPE ID/F, DIGENIC 2005-01-01 no assertion criteria provided literature only
GeneReviews RCV000222140 SCV000268756 not provided Usher syndrome type 1 no assertion provided literature only
Natera, Inc. RCV000222140 SCV001463590 uncertain significance Usher syndrome type 1 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358062 SCV001553706 uncertain significance not provided no assertion criteria provided clinical testing The CDH23 p.Arg86Trp variant was not identified in the Cosmic database but was identified in dbSNP (ID: rs121908353) ClinVar (reported as a VUS by Partners Laboratory for Molecular Medicine), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 6 of 279194 chromosomes at a frequency of 0.000021 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 4 of 10320 chromosomes (freq: 0.000388) and African in 2 of 24024 chromosomes (freq: 0.000083); it was not observed in the Latino, East Asian, European (Finnish), European (non-Finnish), Other, and South Asian populations. Zheng et al. (2005) identified the variant in a proband with deafness who also carried a PCDH15 variant. The p.Arg86 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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