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 pathogenic Rare genetic deafness 2010-02-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000385938 SCV000363840 uncertain significance Retinitis pigmentosa-deafness syndrome 2016-06-14 criteria provided, single submitter clinical testing
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 2018-12-28 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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