Submissions for variant NM_001110792.2(MECP2):c.507C>G (p.Phe169Leu)

dbSNP: rs267608484

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000133127	SCV002769704	pathogenic	Rett syndrome	2022-10-11	reviewed by expert panel	curation	The c.471C>G (p.Phe157Leu) variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 15675358) (PP4). The p.Phe157Leu variant in MECP2 has been observed in 2 additional individuals with MECP2-related conditions (PMID 30536762, RettBASE) (PS4_moderate). The p.Phe157Leu variant occurs in the well-characterized methyl-DNA binding functional domain of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Phe169Leu variant in MECP2 is absent from gnomAD (PM2_supporting). The c.471C>A variant in the MECP2 gene results in a p.Phe157Leu change that is a previously established pathogenic variant (ClinVar, Invitae - internal database) (PS1). A pathogenic missense variant (p.Phe157Ile) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16832102, 27929079, RettBASE) (PM5). In summary, the c.471C>G (p.Phe157Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS1 + PM1 + PM5 + PS4_moderate + PM2_supporting + PP3 + PP4).
Invitae	RCV001385711	SCV001585672	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2020-05-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe157 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been observed in individuals with MECP2-related conditions (PMID: 16832102, 27929079), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This missense variant has been observed in individual(s) with Rett syndrome or neonatal encephalopathy (PMID: 16225173, 15675358, 22476991, 19722030, 30536762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143589). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 157 of the MECP2 protein (p.Phe157Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.
RettBASE	RCV000133127	SCV000188119	uncertain significance	Rett syndrome	2010-01-16	no assertion criteria provided	curation