Submissions for variant NM_001110792.2(MECP2):c.434G>T (p.Arg145Leu)

dbSNP: rs61748389

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000133093	SCV002769702	pathogenic	Rett syndrome	2022-10-11	reviewed by expert panel	curation	The p.Arg133Leu variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome (PMID 10854091) (PM6). The p.Arg133Leu variant has been observed in at least 1 other individual with classic Rett syndrome (PMID 19722030) (PS4_supporting, PP4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 30569584, 23421866, 11738879, 26418480, 16473305, 22368975; ClinVar) (PM5_strong). The p.Arg133Leu 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). MECP2 chromatin binding assays have shown that this variant impacts protein function (PMID 27929079, 22923521) (PS3_supporting). In summary, the p.Arg133Leu variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PM6, PS3_supporting, PS4_supporting, PM2_supporting, PP3 + PP4).
GeneDx	RCV001565841	SCV001789269	pathogenic	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect including reduced transcription, mislocalization, and reduction in heterochromatin binding (Kudo et al., 2003; Sheikh et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21831886, 12843318, 22923521, 25525159, 10854091, 27929079, 32260176, 31629770, 30405208, 30651074, 32579932)
Centre for Population Genomics, CPG	RCV000133093	SCV004232296	pathogenic	Rett syndrome	2024-01-11	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: >=2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6).(PMID 10854091). Computational prediction analysis tools suggests a deleterious impact (REVEL score (0.98) >= 0.75) (PP3). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4).(PMID 19722030) 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 27929079, 22923521.
RettBASE	RCV000133093	SCV000188083	uncertain significance	Rett syndrome	2002-02-15	no assertion criteria provided	curation