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

dbSNP: rs267608387

Total submissions: 5

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