Submissions for variant NM_022124.6(CDH23):c.3262G>A (p.Val1088Met)

gnomAD frequency: 0.00009  dbSNP: rs200632520

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039145	SCV000062829	uncertain significance	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val1088Met va riant in CDH23 has been previously reported in two probands with hearing loss by our laboratory. However, it also has been identified in 0.2% (40/18854) of Eas t Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs200632520). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. This variant has also been reported in ClinVar (Variation ID 45912; Illumi na - VUS). Computational prediction tools and conservation analysis suggest that the p.Val1088Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical si gnificance of the p.Val1088Met variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting.
Illumina Laboratory Services, Illumina	RCV000285498	SCV000363692	uncertain significance	CDH23-Related Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000324074	SCV000363693	uncertain significance	Usher syndrome type 1D	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000376393	SCV000363694	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV000764914	SCV000896077	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001041387	SCV001205000	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000324074	SCV001572160	uncertain significance	Usher syndrome type 1D	2021-04-08	criteria provided, single submitter	research	The CDH23 c.3262G>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. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx	RCV001041387	SCV001794342	uncertain significance	not provided	2021-01-07	criteria provided, single submitter	clinical testing	Reported in a patient with a pituitary adenoma in the published literature (Zhang et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28413019)
PreventionGenetics, part of Exact Sciences	RCV003904936	SCV004726596	likely benign	CDH23-related condition	2023-07-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001271862	SCV001453335	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing