Submissions for variant NM_022124.6(CDH23):c.7362G>A (p.Thr2454=)

gnomAD frequency: 0.00006  dbSNP: rs370983472

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039265	SCV000062949	likely pathogenic	Rare genetic deafness	2013-04-01	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000483242	SCV000568534	likely pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 22135276, 34428318)
Eurofins Ntd Llc (ga)	RCV000483242	SCV000859356	likely pathogenic	not provided	2018-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000483242	SCV001495279	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects codon 2454 of the CDH23 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH23 protein. This variant also falls at the last nucleotide of exon 52, which is part of the consensus splice site for this exon. This variant is present in population databases (rs370983472, gnomAD 0.004%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22135276; Invitae). ClinVar contains an entry for this variant (Variation ID: 46029). 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.
3billion	RCV002250505	SCV002521145	uncertain significance	Usher syndrome type 1D	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tools do not predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.07). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22135276). The variant has been reported to be associated with CDH23 related disorder (ClinVar ID: VCV000046029), but the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330411	SCV004037649	likely pathogenic	Usher syndrome	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.7362G>A (p.Thr2454Thr) alters a conserved nucleotide located close to a canonical splice site, specifically the last nucleotide of Exon 52, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, and one predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249280 control chromosomes (gnomAD). c.7362G>A has been reported in the literature in multiple compound heterozygous individuals affected with Usher Syndrome (e.g., Le Quesne Stabej_2012, Usami_2022, Feenstra_2022, Nizamudheen_2021 (no PMID)). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36011334, 22135276, 35020051). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (likely pathogenic, n = 3; pathogenic, n = 1; uncertain significance, n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003473284	SCV004210626	likely pathogenic	Pituitary adenoma 5, multiple types	2023-08-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274911	SCV001459464	likely pathogenic	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing