Submissions for variant NM_022124.6(CDH23):c.6049G>A (p.Gly2017Ser)

gnomAD frequency: 0.00001  dbSNP: rs183431253

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039235	SCV000062919	likely pathogenic	Rare genetic deafness	2011-11-23	criteria provided, single submitter	clinical testing	The Gly2017Ser variant in CDH23 has been reported in 2 probands with Usher synd rome type I and was absent from 192 control chromosomes (Oshima 2008, Roux 2006) . One of these probands was homozygous and the other was compound heterozygous w ith another pathogenic CDH23 variant. The Gly2017Ser variant occurs in the last base of the exon. This position has been shown to be part of the splicing consen sus sequence and splicing prediction models predict that this variant could affe ct splicing. In summary, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763216	SCV000893842	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377826	SCV001575261	pathogenic	not provided	2024-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2017 of the CDH23 protein (p.Gly2017Ser). This variant also falls at the last nucleotide of exon 46, which is part of the consensus splice site for this exon. This variant is present in population databases (rs183431253, gnomAD 0.02%). This missense change has been observed in individuals with Usher syndrome (PMID: 18323324, 23451239, 25404053). ClinVar contains an entry for this variant (Variation ID: 46000). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Studies have shown that this missense change alters CDH23 gene expression (PMID: 23451239). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001377826	SCV001812919	likely pathogenic	not provided	2021-07-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging splicing effect with skipping of exon 46 likely resulting in nonsense-mediated decay (Aparisi et al., 2013); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32488467, 23451239, 16679490, 27535533, 18429043, 25404053, 18323324, 25525159)
Baylor Genetics	RCV003473280	SCV004210611	pathogenic	Pituitary adenoma 5, multiple types	2023-09-25	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376240	SCV001573313	uncertain significance	Usher syndrome type 1D	2021-04-08	flagged submission	research	The CDH23 c.6049G>A 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, PM3, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Clinical Genetics, Academic Medical Center	RCV001377826	SCV001921507	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001377826	SCV001953094	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004757122	SCV005349484	likely pathogenic	CDH23-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The CDH23 c.6049G>A variant is predicted to result in the amino acid substitution p.Gly2017Ser. This variant has been reported in patients with autosomal recessive Usher syndrome (Aparisi et al 2014. PubMed ID: 25404053; Colombo et al 2021. PubMed ID: 33576794; Table S5, Roux et al 2006. PubMed ID: 16679490; Aparisi et al 2013. PubMed ID: 23451239; Oshima et al 2008. PubMed ID: 18429043). This variant occurs at the last nucleotide of exon 46, and functional in vitro assays have shown that it results in exon skipping while RT-PCR results from nasal epithelial cells found no evidence of the transcript lacking exon 46, suggestive of nonsense mediated decay (Aparisi et al 2013. PubMed ID: 23451239). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.