Submissions for variant NM_022124.6(CDH23):c.9565C>T (p.Arg3189Trp) (rs121908353)

Total submissions: 6

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	2019-10-18	reviewed by expert panel	curation	The c.9565C>T (p.Arg3189Trp) variant in CDH23 has been identified in 2 heterozygous patients with Usher syndrome without another CDH23 variant in trans (Partners LMM internal data, SCV000062996.5; PMID 22381527, 18395802). This variant was identified in 4/10120 (0.00040) Ashkenazi Jewish alleles in gnomAD. This is above the BS1 autosomal recessive threshold of 0.02% of alleles. However the filtering allele frequency of the variant is 0.00003979. Which is less than the BS1_Supporting threshold (BS1/PM2 not met). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own. A different missense variant (p.Arg3189Gln) has been previously identified at this codon of CDH23, however this variant does not have enough evidence to support pathogenicity (PM5 not met; ClinVar Variation ID 162956). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3.
Laboratory for Molecular Medicine, Partners HealthCare 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.
OMIM	RCV000005209	SCV000025386	pathogenic	USHER SYNDROME, TYPE ID/F, DIGENIC	2005-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000222140	SCV000268756	pathogenic	Usher syndrome type 1	2016-05-19	no assertion criteria 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.