ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.1919C>T (p.Thr640Met)

gnomAD frequency: 0.00011  dbSNP: rs199796910
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000175363 SCV000226836 uncertain significance not provided 2017-01-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000175363 SCV001418594 uncertain significance not provided 2022-10-23 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 640 of the CDH23 protein (p.Thr640Met). This variant is present in population databases (rs199796910, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness or Usher syndrome (PMID: 22135276, 26969326). ClinVar contains an entry for this variant (Variation ID: 194889). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function. 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.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376241 SCV001573314 uncertain significance Usher syndrome type 1D 2021-04-08 criteria provided, single submitter research The CDH23 c.1919C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx RCV000175363 SCV001817561 uncertain significance not provided 2024-11-13 criteria provided, single submitter clinical testing Reported in a patient with hearing loss in published literature with limited evidence for pathogenicity (PMID: 26969326); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22135276, 26969326, 34906470)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265660 SCV002547555 uncertain significance not specified 2022-05-17 criteria provided, single submitter clinical testing Variant summary: CDH23 c.1919C>T (p.Thr640Met) results in a non-conservative amino acid change located in the Cadherin 6 domain (562-671, LOVD) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 247720 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CDH23 causing Usher Syndrome (0.00016 vs 0.0032), allowing no conclusion about variant significance. c.1919C>T has been reported in the literature in individuals affected with Usher Syndrome and Autosomal recessive non-syndromic hearing loss (Le Quesne Stabej_2011, Sloan-Heggen_2016). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002492744 SCV002796923 uncertain significance Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types 2021-07-16 criteria provided, single submitter clinical testing
Natera, Inc. RCV001826885 SCV002094407 uncertain significance Usher syndrome type 1 2020-03-16 no assertion criteria provided clinical testing

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