ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.513C>A (p.Tyr171Ter) (rs267608490)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, ClinGen RCV001507047 SCV001712003 pathogenic CDKL5 disorder 2021-03-09 reviewed by expert panel curation The p.Tyr171* variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Tyr171* variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with CDKL5 disorder (PMID 23583054) (PM6. This variant has been observed in at least 1 other individual with CDKL5 disorder (ClinVar) (PS4_Supporting). This variant was absent from gnomAD (PM2_ Supporting). In summary, p.Tyr171* variant in CDKL5 is classified as Pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PVS1, PM6, PM2_Supporting, PS4_Supporting).
GeneDx RCV000133371 SCV000190956 pathogenic not provided 2017-03-03 criteria provided, single submitter clinical testing The c.513 C>A variant, resulting in the Y171X nonsense variant in the CDKL5 gene, has beenreported previously as a de novo finding in a male with early-onset epilepsy (Mirzaa et al., 2013).This variant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. This variant is not observed in large population cohorts (Lek et al.,2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, a differentnucleotide substitution (c.513 C>G) that also results in the Y171X nonsense variant was previouslyidentified in a female with features of a CDKL5-related disorder (Sartori et al., 2011). We interpretY171X as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000145541 SCV000192633 pathogenic Early infantile epileptic encephalopathy 2 2013-02-08 criteria provided, single submitter clinical testing
RettBASE RCV000145541 SCV000188385 pathogenic Early infantile epileptic encephalopathy 2 2014-03-13 no assertion criteria provided curation Early truncation, partial loss the phophorylation site

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