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

gnomAD frequency: 0.00001  dbSNP: rs771353319

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778287	SCV000914465	uncertain significance	Autosomal recessive nonsyndromic hearing loss 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	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1554 of the CDH23 protein (p.Asp1554Glu). This variant is present in population databases (rs771353319, gnomAD 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 21940737). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 Available"; 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 Laboratory Services, 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, Mass General Brigham 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.
GeneDx	RCV001061690	SCV003933415	likely pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21940737)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001195596	SCV004029649	uncertain significance	not specified	2023-07-07	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.4662C>A (p.Asp1554Glu) results in a conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245388 control chromosomes (gnomAD). c.4662C>A has been reported in the literature in two related individuals affected with nonsyndromic deafness who had other (likely) pathogenic variants in trans (Schultz_2011). Two other members of this family were compound heterozygous with other variants and were diagnosed with Usher syndrome type 1. These data indicate that the variant may be associated with with a milder form of disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21940737). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV001272899	SCV001455323	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing