ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.414-2A>C

dbSNP: rs267608464
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Population Genomics, CPG RCV000170198 SCV004809012 pathogenic Rett syndrome 2024-03-14 criteria provided, single submitter curation This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome with confirmed parental relationships (PS2) PMID: 11309679 This variant is absent from gnomAD (PM2_Supporting). Has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting). PMID: 11309679, PMID: 27267200
RettBASE RCV000144112 SCV000189188 not provided not provided flagged submission not provided
RettBASE RCV000170198 SCV000222527 pathogenic Rett syndrome 2003-03-31 no assertion criteria provided curation
PreventionGenetics, part of Exact Sciences RCV004532624 SCV004748235 pathogenic MECP2-related disorder 2023-12-08 no assertion criteria provided clinical testing The MECP2 c.378-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with Rett syndrome and mRNA analysis further confirmed a deletion caused by abnormal splicing (Bourdon et al 2001. PubMed ID: 11214906). Of note, other splicing variants affecting the same nucleotide (c.378-2A>G, c.378-2A.T) have also been reported to be causative for Rett syndrome (HGMD database, Wen et al. 2020. PubMed ID: 32472557). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic.

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