ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.5038G>A (p.Val1680Ile)

gnomAD frequency: 0.00044  dbSNP: rs201364852
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000150297 SCV000197356 likely benign not specified 2013-07-28 criteria provided, single submitter clinical testing Val1680Ile in Exon 39 of CDH23: This variant is not expected to have clinical si gnificance because the valine (Val) residue at position 1680 is poorly conserved across species, with many vertebrate, mammalian and primate species (including chimpanzee, gorilla, and orangutan) having an isoleucine (Ile) at this position. In addition, it has been identified in 0.01% (1/8566) of European American chr omosomes and 0.05% (2/4382) of African American chromosomes from a broad populat ion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; db SNP rs201364852).
Invitae RCV001059410 SCV001224034 likely benign not provided 2024-01-20 criteria provided, single submitter clinical testing
GeneDx RCV001059410 SCV001793885 uncertain significance not provided 2020-12-30 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001059410 SCV001552703 uncertain significance not provided no assertion criteria provided clinical testing The CDH23 p.Val1680Ile variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs201364852) and ClinVar (classified as likely benign by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine). The variant was also identified in control databases in 35 of 280646 chromosomes at a frequency of 0.000125 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 22 of 24270 chromosomes (freq: 0.000907), European (non-Finnish) in 9 of 128346 chromosomes (freq: 0.00007), Latino in 2 of 35374 chromosomes (freq: 0.000057), East Asian in 1 of 19532 chromosomes (freq: 0.000051), and South Asian in 1 of 30600 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish, European (Finnish), or other populations. The p.Val1680 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing at the variant location. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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