ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.416C>T (p.Pro139Leu)

dbSNP: rs267608387
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Total submissions: 5
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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 RCV000133085 SCV002047364 pathogenic Rett syndrome 2021-10-26 reviewed by expert panel curation The p.Pro127Leu variant in MECP2 (NM_004992.3) has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID: 16225173, 22182064) (PM6_strong, PP4). This variant has been observed in at least 5 other individuals with Rett syndrome (PMID: 11245712, 16473305, 11960578, internal database - Invitae) (PS4). The p.Pro127Leu variant occurs in the well-characterized methyl binding domain (MBD) functional domain of MECP2 (PMID: 21326358, 23770565) (PM1). The p.Pro127Leu variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro127Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4, PM1, PM2_supporting, PP3, PP4).
Invitae RCV000531543 SCV000645664 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2021-05-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this this missense change did not affect MECP2 accumulation at chromocenters or MECP2 transcriptional repressive activity in cultured cells (PMID: 21831886, 12843318). This variant has been reported in two individuals affected with classical Rett syndrome (PMID: 16225173, 11960578) and an individual affected with the rare preserved speech variant of Rett syndrome (PMID: 11245712). This variant has also been shown to arise de novo in an individual affected with Rett syndrome (PMID: 20376788, 22182064). ClinVar contains an entry for this variant (Variation ID: 143552). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 127 of the MECP2 protein (p.Pro127Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
Centre for Population Genomics, CPG RCV000133085 SCV004232243 pathogenic Rett syndrome 2024-01-09 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: 16225173, 17089071, 22182064 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 16473305, 16225173, 11245712, 20207612, 11960578, 17089071). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
RettBASE RCV000133085 SCV000188074 uncertain significance Rett syndrome 2010-07-13 no assertion criteria provided curation
Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University RCV000133085 SCV003838971 pathogenic Rett syndrome no assertion criteria provided clinical testing

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