ClinVar Miner

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

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Total submissions: 8
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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 2020-01-15 criteria provided, single submitter clinical testing The p.Glu2490Lys variant in CDH23 has been identified in 4 individuals with non-syndromic hearing loss; however, 3 of these individuals did not carry a second CDH23 variant (Kothiyal 2010, Sloan Heggen 2016, LMM data). It has also been identified in 0.05% (69/128346) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 46032). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
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
Invitae RCV000725960 SCV001232452 uncertain significance not provided 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2490 of the CDH23 protein (p.Glu2490Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs41281336, ExAC 0.04%). This variant has been observed in individuals affected with Usher syndrome or hearing loss (PMID: 26969326, 20146813). This variant is also known as NM_001171933:c.748G>A (p.Glu250Lys) in the literature. ClinVar contains an entry for this variant (Variation ID: 46032). 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 C55"). 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 RCV001108080 SCV001265275 uncertain significance Deafness, autosomal recessive 12 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001108081 SCV001265276 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.

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