ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.7468G>A (p.Glu2490Lys) (rs41281336)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039268 SCV000062952 uncertain significance not specified 2013-12-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Glu2490Lys vari ant in CDH23 has now been identified by our laboratory in three individuals with hearing loss, none of whom had a second CDH23 variant. This variant has been id entified in 4/8300 European American chromosomes and 1/3992 African American chr omosomes by the NHLBI Exome Sequening Project (; dbS NP rs41281336) and in 6/2178 (0.3%) chromosomes by the 1000 Genomes Project (htt p:// Although this variant has been seen in the general pop ulation, its frequency is not high enough to rule out a pathogenic role. Computa tional analyses (biochemical amino acid properties, conservation, AlignGVGD, Pol yPhen2, MAPP, MutationTaster, and SIFT) suggest this variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, additional information is needed to determine the clinical signifi cance of this variant; however, based upon the frequency in the general populati on and the absence of a second variant in cases, we would lean towards a more li kely benign role.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725960 SCV000340860 uncertain significance not provided 2016-04-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000039268 SCV000885164 uncertain significance not specified 2018-12-05 criteria provided, single submitter clinical testing The p.Glu2490Lys variant (rs41281336) was reported in two individuals from cohort studies with non-syndromic hearing loss (Sloan-Heggen 2016 and Kothiyal 2010). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.03 percent (identified on 87 out of 276,976 chromosomes) and has been reported to the ClinVar database as a variant of uncertain significance (Variation ID: 46032). The glutamic acid at position 2,490 is highly conserved up to zebrafish considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Glu2490Lys variant on protein structure and function provide conflicting results (SIFT: tolerated, GVGD: class C55, PolyPhen-2:possibly damaging). Altogether, there is not enough evidence to classify the p.Glu2490Lys variant with certainty.
Fulgent Genetics,Fulgent Genetics RCV000763667 SCV000894547 uncertain significance Deafness, autosomal recessive 12; Usher syndrome, type 1D; PITUITARY ADENOMA 5, MULTIPLE TYPES 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725960 SCV001147965 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing

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