ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.6442G>A (p.Asp2148Asn) (rs111033271)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000599622 SCV000062930 likely pathogenic Rare genetic deafness 2019-06-10 criteria provided, single submitter clinical testing The p.Asp2148Asn variant in CDH23 has been previously reported in 1 individual with Usher syndrome who was compound heterozygous with p.Trp2811* (Bonnet 2016). It has also been reported in 4 additional individuals with hearing loss without evidence of retinitis pigmentosa and segregated in four affected relatives (Astuto 2002, de Brouwer 2003, Pennings 2004, Schultz 2003). In one study, the variant was identified in one Dutch patient who was homozygous, and in an American patient who was compound heterozygous with p.R2608H (reported as uncertain and likely benign in ClinVar) (Astuto 2002). In another large family with hearing loss, the p.Asp2148Asn variant was identified in four family members with hearing loss; two siblings were homozygous and two other individuals were compound heterozygous (with p.D1341N) (de Brouwer 2003, Pennings 2004). The variant was also reported in two siblings with hearing loss who were compound heterozygous with p.Arg1746Gln (Schultz 2011). This variant has been identified in 0.01% (25/128344) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss, and there could be a risk for Usher syndrome associated with this variant when present in compound heterozygosity with a loss of function variant as was reported in Bonnet 2016. ACMG/AMP criteria applied: PP1_Strong, PM3, PM2_Supporting, PP3.
Illumina Clinical Services Laboratory,Illumina RCV000385938 SCV000363840 uncertain significance Usher syndrome type 1D 2017-04-27 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.
Illumina Clinical Services Laboratory,Illumina RCV000005204 SCV000363841 pathogenic Deafness, autosomal recessive 12 2018-05-03 criteria provided, single submitter clinical testing The CDH23 c.6442G>A (p.Asp2148Asn) missense variant has been reported in three studies in which it is found in a total of eight individuals with hearing loss, including in two in a homozygous state, in five in a compound heterozygous state, and in one where zygosity was not specified (Astuto et al. 2002; De Brouwer et al. 2003; Schultz et al. 2011). This variant was also identified in 14 unaffected individuals in a heterozygous state. The p.Asp2148Asn variant was absent from a total of 296 controls and is reported at a frequency of 0.00015 in the European (non-Finnish) population of Exome Aggregation Consortium. Protein modelling studies revealed the Asp2148 residue is conserved and located in a calcium binding domain. Other aspartic acid to asparagine substitions associated with disease have been reported in these domains (de Brouwer et al. 2003). Based on the evidence, the p.Asp2148Asn variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Molecular Diagnostics Laboratory, M Health: University of Minnesota RCV000710063 SCV000840448 pathogenic Deafness, autosomal recessive 12; Usher syndrome, type 2A 2016-10-05 criteria provided, single submitter clinical testing
Invitae RCV000809058 SCV000949195 likely pathogenic not provided 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 2148 of the CDH23 protein (p.Asp2148Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs111033271, ExAC 0.02%). This variant has been observed to segregate with sensorineural hearing impairment in families (PMID: 12522556, 21940737). It was also reported in unrelated individuals affected with sensorineural hearing impairment (PMID: 12075507, 21940737, 12522556) and with Usher syndrome (PMID: 27460420). ClinVar contains an entry for this variant (Variation ID: 4922). 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 C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000005204 SCV000025381 pathogenic Deafness, autosomal recessive 12 2003-02-01 no assertion criteria provided literature only

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