ClinVar Miner

Submissions for variant NM_000330.4(RS1):c.185-3221G>A

dbSNP: rs374054249
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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 RCV003448375 SCV004176227 likely benign CDKL5 disorder 2023-12-06 reviewed by expert panel curation RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2941C>T (p.Arg981Ter) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3221G>A) is present in 14 XX and 7 XY individuals in gnomAD v4 (0.0043%) (not sufficient to meet BS1 criteria). The p.Arg981Ter 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. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (not sufficient to meet PVS1 criteria). Additionally, the p.Arg981Ter variant is observed in at least 6 unaffected individuals (internal database - Invitae, internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Arg981Ter variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS2).
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001196426 SCV001367034 uncertain significance Developmental and epileptic encephalopathy, 2 2020-02-04 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in hemizygous state.
Invitae RCV001247832 SCV001421278 likely benign Developmental and epileptic encephalopathy, 2; Angelman syndrome-like 2023-04-12 criteria provided, single submitter clinical testing
Mendelics RCV002249780 SCV002518058 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing

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