ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1344_1345del (p.Gln449fs)

dbSNP: rs61753972
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000132985 SCV000778314 pathogenic Rett syndrome 2018-06-01 criteria provided, single submitter clinical testing
Invitae RCV000690876 SCV000818605 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2023-10-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln437Alafs*49) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 11055898; Invitae). This variant is also known as c.1308delTC and c.1308_1309del2. ClinVar contains an entry for this variant (Variation ID: 143457). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Ala439Glyfs*47, p.Tyr450Leufs*37) have been determined to be pathogenic (PMID: 10814718, 16473305, 19914908, 23696494). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Centre for Population Genomics, CPG RCV000132985 SCV004098741 pathogenic Rett syndrome 2023-08-14 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 2.0, 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 is absent from gnomAD (PM2_Supporting).It has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting, PMID: 11055898, RettBase internal database).
RettBASE RCV000132985 SCV000187969 pathogenic Rett syndrome 2002-04-10 no assertion criteria provided curation

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