Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
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 | |
Gene |
RCV000222140 | SCV000268756 | pathogenic | Usher syndrome type 1 | 2016-05-19 | no assertion criteria provided | literature only | |
Natera, |
RCV000222140 | SCV001463590 | uncertain significance | Usher syndrome type 1 | 2020-09-16 | no assertion criteria provided | clinical testing |