ClinVar Miner

Submissions for variant NM_001323289.2(CDKL5):c.1247_1248del (p.Glu416fs) (rs786204967)

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Total submissions: 6
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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 RCV001507057 SCV001712024 pathogenic CDKL5 disorder 2021-03-26 reviewed by expert panel curation The p.Glu416Valfs variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Glu416Valfs variant has been observed in at least 5 individuals with CDKL5 disease (PMID: 27779742, 27864847, 23064044, ClinVar Variation ID 189554) (PS4). The p.XX variant in GENE has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with CDKL5 disorder (PMID XX) (PMID 27779742, 27864847) (PM6_strong). This variant is absent from gnomAD (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria applied (PVS1, PS4, PM6_strong, PM2_supporting).
GeneDx RCV000169994 SCV000329687 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing The c.1247_1248delAG pathogenic variant in the CDKL5 gene has been reported previously in an individual with epileptic encephalopathy (Raymond et al., 2013). The c.1247_1248delAG variant causes a frameshift starting with codon Glutamic Acid 416, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Glu416ValfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1247_1248delAG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1247_1248delAG as a pathogenic variant.
Neurogenetics Laboratory - MEYER, AOU Meyer RCV000416945 SCV000494537 pathogenic Epileptic encephalopathy 2016-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624117 SCV000740941 pathogenic Inborn genetic diseases 2015-06-09 criteria provided, single submitter clinical testing
Invitae RCV001385705 SCV001585665 pathogenic Early infantile epileptic encephalopathy 2; Angelman syndrome-like 2020-07-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu416Valfs*2) in the CDKL5 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of CDKL5-related conditions (PMID: 27779742, 30945278, 31164858, 23064044). In at least one individual the variant was observed to be de novo. This variant is also known as c.1245_1246delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 189554). Loss-of-function variants in CDKL5 are known to be pathogenic (PMID: 22872100). For these reasons, this variant has been classified as Pathogenic.
RettBASE RCV000169994 SCV000222300 pathogenic not provided 2014-03-13 no assertion criteria provided curation

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