Submissions for variant NM_022124.6(CDH23):c.7468G>A (p.Glu2490Lys)

gnomAD frequency: 0.00035  dbSNP: rs41281336

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039268	SCV000062952	uncertain significance	not specified	2020-01-15	criteria provided, single submitter	clinical testing	The p.Glu2490Lys variant in CDH23 has been identified in 4 individuals with non-syndromic hearing loss; however, 3 of these individuals did not carry a second CDH23 variant (Kothiyal 2010, Sloan Heggen 2016, LMM data). It has also been identified in 0.05% (69/128346) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 46032). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Eurofins Ntd Llc (ga)	RCV000725960	SCV000340860	uncertain significance	not provided	2016-04-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000039268	SCV000885164	uncertain significance	not specified	2018-12-05	criteria provided, single submitter	clinical testing	The p.Glu2490Lys variant (rs41281336) was reported in two individuals from cohort studies with non-syndromic hearing loss (Sloan-Heggen 2016 and Kothiyal 2010). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.03 percent (identified on 87 out of 276,976 chromosomes) and has been reported to the ClinVar database as a variant of uncertain significance (Variation ID: 46032). The glutamic acid at position 2,490 is highly conserved up to zebrafish considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Glu2490Lys variant on protein structure and function provide conflicting results (SIFT: tolerated, GVGD: class C55, PolyPhen-2:possibly damaging). Altogether, there is not enough evidence to classify the p.Glu2490Lys variant with certainty.
Fulgent Genetics, Fulgent Genetics	RCV000763667	SCV000894547	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2021-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725960	SCV001147965	uncertain significance	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV000725960	SCV001232452	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108080	SCV001265275	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001108081	SCV001265276	uncertain significance	Usher syndrome type 1D	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001108080	SCV001781496	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001108081	SCV001781497	uncertain significance	Usher syndrome type 1D	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000725960	SCV002073998	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing	Observed with a second variant (phase unknown) in a patient with Usher syndrome in published literature (Sloan-Heggen et al., 2016); however, clinical information is limited; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20146813, 34426522, 26969326)
Mayo Clinic Laboratories, Mayo Clinic	RCV000725960	SCV004225274	uncertain significance	not provided	2022-03-22	criteria provided, single submitter	clinical testing	PM2_supporting
Natera, Inc.	RCV001276040	SCV001461868	uncertain significance	Usher syndrome type 1	2020-04-17	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000725960	SCV001953178	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725960	SCV001974071	uncertain significance	not provided		no assertion criteria provided	clinical testing