Submissions for variant NM_022124.6(CDH23):c.7552G>A (p.Val2518Met)

gnomAD frequency: 0.00011  dbSNP: rs376617494

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150319	SCV000197407	uncertain significance	not specified	2014-05-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val2518Met vari ant in CDH23 has not been previously reported in individuals with hearing loss, but has been identified in 0.01% (1/8388) of European American chromosomes by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs376 617494). Although this variant has been seen in the general population, its freq uency is not high enough to rule out a pathogenic role. The valine (Val) residue at position 2518 is highly conserved in mammals and evolutionary distant specie s, but several turtle species carry a methionine (Met) at this position, raising the possibility that this change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an i mpact to the protein. In summary, while the clinical significance of the Val2518 Met variant is uncertain, the conservation data suggest that is more likely to b e benign.
Illumina Laboratory Services, Illumina	RCV000368231	SCV000363871	uncertain significance	CDH23-Related Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000275931	SCV000363872	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-13	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	RCV000314616	SCV000363873	uncertain significance	Usher syndrome type 1D	2018-01-13	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.
GeneDx	RCV000658566	SCV000618170	uncertain significance	not provided	2018-04-26	criteria provided, single submitter	clinical testing	The V2518M variant in the CDH23 gene has been reported previously, using alternate nomenclature of V278M, along with a second CDH23 variant in a child with autosomal recessive non-syndromic congenital hearing loss (Sloan-Heggen et al., 2016). This variant is observed in 5/66,704 alleles (0.0075%) from individuals of non-Finnish European background, and 1/9,800 alleles (0.01%) from individuals of African background, in the ExAC dataset (Lek et al., 2016). The V2518M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V2518M as a variant of uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000658566	SCV000780342	uncertain significance	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375197	SCV001571851	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Moderate, PP3_Supporting, BP5_Supporting
Fulgent Genetics, Fulgent Genetics	RCV002498689	SCV002814018	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2021-08-25	criteria provided, single submitter	clinical testing
Invitae	RCV000658566	SCV003260643	uncertain significance	not provided	2022-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2518 of the CDH23 protein (p.Val2518Met). This variant is present in population databases (rs376617494, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 162943). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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.
Natera, Inc.	RCV001276912	SCV001463569	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing