ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.4662C>A (p.Asp1554Glu) (rs771353319)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778287 SCV000914465 uncertain significance Deafness, autosomal recessive 12 2017-09-06 criteria provided, single submitter clinical testing The CDH23 c.4662C>A (p.Asp1554Glu)missense variant has been reported in a single study in which it is identified in a compound heterozygous state in two related individuals with nonsyndromic hearing loss (Schultz et al. 2011). Both individuals, a father and daughter, were reported to present with sensorineural hearing loss. The mother and another daughter were reported to have Usher syndrome and also found to carry compound heterozygous variants in CDH23, though notably, the p.Asp1554Glu variant was only identified in family members with the nonsyndromic hearing loss phenotype in trans with CDH23 variants associated with Usher syndrome in other family members, suggesting it may have a more moderate impact on gene function. The p.Asp1554Glu variant was absent from 718 controls but is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, p.Asp1554Glu variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001061690 SCV001226441 uncertain significance not provided 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 1554 of the CDH23 protein (p.Asp1554Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs771353319, ExAC 0.002%). This variant has been observed in individual(s) with non-syndromic deafness (PMID: 21940737). ClinVar contains an entry for this variant (Variation ID: 631639). 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 Availabe"; Align-GVGD: "Class C35"). 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.
Illumina Clinical Services Laboratory,Illumina RCV001107534 SCV001264687 uncertain significance Usher syndrome type 1D 2017-08-21 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195596 SCV001365995 uncertain significance not specified 2019-12-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp1554Glu variant in CDH23 has been previously reported in 1 proband and her father with nonsyndromic hearing loss who were each compound heterozygous for a second CDH23 variant (Schultz 2011). Of interest, the proband's mother and brother had clinical features of Usher syndrome due to additional CDH23 variants; however, the p.Asp1554Glu variant was only observed in the family members with nonsydromic hearing loss suggesting that it may be associated with the DFNB12 nonsyndromic hearing loss phenotype. This variant was identified in 0.003% (3/111102) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PP3.

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