Submissions for variant NM_022124.6(CDH23):c.2239C>T (p.Arg747Cys)

gnomAD frequency: 0.00136  dbSNP: rs200649500

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039123	SCV000062805	likely benign	not specified	2017-05-18	criteria provided, single submitter	clinical testing	p.Arg747Cys in exon 21 of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (247/126652) of European chro mosomes including one homozygote by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs200649500). It has been observed in 4 ind ividuals with alternate explanations for their hearing loss (Roux 2011, LMM Data ), including 1 individual who had a pathogenic truncating CDH23 variant in cis w ith this variant (https://grenada.lumc.nl: Patient ID FR0145311510; Roux 2011). This variant has also been observed in 5 additional individuals with hearing los s; however, a variant affecting the remaining copy of CDH23 was not identified ( Shearer 2013, LMM Data). In summary, given its relatively high frequency in the general population, multiple reports of the variant in individuals with alterna te etiologies, its presence in cis with a pathogenic CDH23 variant, and the fact that it has never been observed in trans with a clearly pathogenic CDH23 varian t in affected individuals, this variant is likely benign.
Illumina Laboratory Services, Illumina	RCV000377652	SCV000363631	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	RCV000283099	SCV000363632	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755905	SCV000883555	uncertain significance	not provided	2017-05-12	criteria provided, single submitter	clinical testing	The p.Arg747Cys variant (rs200649500) has been previously identified in a hearing loss cohort (Shearer et al. 2013) but was not identified in a patient with 2nd pathogenic variant of CDH23. This variant has been reported to ClinVar (Variation ID: 45890). The p.Arg747Cys variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.18 percent (identified on 22 out of 12,542 chromosomes) and is listed in the Genome Aggregation Database (gnomAD) with a European (Non-Finnish) population frequency of 0.20 percent (identified on 247 out of 126,652 chromosomes, including 1 homozygote). The arginine at position 747 is highly conserved, up to Zebrafish (considering 12 species) (Alamut v2.10) and computational analyses of the effects of the p.Arg747Cys variant on protein structure and function predict a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Arg747Cys variant with certainty.
Invitae	RCV000755905	SCV001038604	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000755905	SCV001143502	likely benign	not provided	2019-04-16	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197523	SCV001368302	uncertain significance	Pituitary adenoma 5, multiple types	2019-09-16	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
GeneDx	RCV000755905	SCV001813197	likely benign	not provided	2020-09-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21436283, 24875298, 23804846)
CeGaT Center for Human Genetics Tuebingen	RCV000755905	SCV002563012	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	CDH23: BS1:Supporting
PreventionGenetics, part of Exact Sciences	RCV004534824	SCV004729660	likely benign	CDH23-related disorder	2024-02-21	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.	RCV001275938	SCV001461618	uncertain significance	Usher syndrome type 1	2020-04-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000755905	SCV001549341	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CDH23 p.Arg747Cys variant was identified in 1 of 260 proband chromosomes (frequency: 0.00385) from individuals with nonsyndromic hearing loss and was present in 1 of 18 control chromosomes (frequency: 0.056) from healthy individuals (Vona_2014_PMID:24875298; Shearer_2013_PMID:23804846). The variant was identified in dbSNP (ID: rs200649500) and ClinVar (classified as uncertain significance by Illumina and ARUP Laboratories, and as likely benign by Laboratory for Molecular Medicine). Laboratory for Molecular Medicine reported this variant in an individual with Usher syndrome who carried another pathogenic CDH23 variant in cis, as well as in other individuals with alternate explanations for their hearing loss. The variant was identified in control databases in 304 of 280334 chromosomes (1 homozygous) at a frequency of 0.001084 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 255 of 128328 chromosomes (freq: 0.001987), Other in 6 of 7134 chromosomes (freq: 0.000841), African in 16 of 24150 chromosomes (freq: 0.000663), Latino in 16 of 35354 chromosomes (freq: 0.000453), South Asian in 7 of 30590 chromosomes (freq: 0.000229) and European (Finnish) in 4 of 24894 chromosomes (freq: 0.000161), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg747 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000755905	SCV001952719	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000755905	SCV001964699	uncertain significance	not provided		no assertion criteria provided	clinical testing