ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.2239C>T (p.Arg747Cys) (rs200649500)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Clinical Services Laboratory,Illumina RCV000377652 SCV000363631 uncertain significance Deafness, autosomal recessive 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 Clinical Services Laboratory,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 2019-12-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc 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 Photophobia; Reduced visual acuity; Macular dystrophy; Metamorphopsia 2019-09-16 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3. This variant was detected in heterozygous state.

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