ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.408G>C (p.Leu136Phe)

dbSNP: rs61755763
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Total submissions: 3
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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 RCV000133082 SCV002769700 pathogenic Rett syndrome 2022-10-11 reviewed by expert panel curation The c.372G>C (p.Leu124Phe) variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 10991688) (PM6). The c.372G>C (p.Leu124Phe) variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). The c.372G>C (p.Leu124Phe) variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 heterochromatin binding assay and in vitro transcriptional repression assay have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). The c.372G>T variant in the MECP2 gene results in a p.Leu124Phe change that is a previously established pathogenic variant (internal database - Invitae) (PS1). In summary, the c.372G>C (p.Leu124Phe) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1, PM1, PM6, PM2_supporting, PS3_supporting).
Centre for Population Genomics, CPG RCV000133082 SCV004808729 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: This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). (PMID: 15737703, 10991688) Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). PMID: 15737703, 11738864, 10991688, 20728410) This variant is absent from gnomAD (PM2_Supporting). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). (PMID: 36253345, 12843318)
RettBASE RCV000133082 SCV000188070 uncertain significance Rett syndrome 2008-01-21 no assertion criteria provided curation

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