ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.2236G>A (p.Val746Ile) (rs550384315)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764912 SCV000896075 uncertain significance Deafness, autosomal recessive 12; Usher syndrome, type 1D; PITUITARY ADENOMA 5, MULTIPLE TYPES 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000657974 SCV000779745 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing The V746I variant has been published as a variant identified in a healthy control group (Oshima et al., 2008). The V746I variant is observed in 27/18866 (0.0152%) alleles from East Asian background in large population cohorts (Lek et al., 2016). This variant has been observed internally in the homozygous state in an apparently unaffected individual. The V746I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150283 SCV000197308 uncertain significance not specified 2013-06-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Val746Ile varia nt in CDH23 has not been reported in individuals with hearing loss or in large p opulation studies. Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Of note, frog has a isoleucine (Ile) at this position despite high nearby amino acid conservation. In summary, the clinical s ignificance of this variant cannot be determined with certainty; however, based upon the arguments described above, we would lean towards a more likely benign r ole.

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