Submissions for variant NM_001110792.2(MECP2):c.946A>G (p.Lys316Glu)

dbSNP: rs61751440

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	RCV000133286	SCV002769705	likely pathogenic	Rett syndrome	2022-10-11	reviewed by expert panel	curation	The p.Lys304Glu variant in MECP2 (NM_004992.3) has been observed in at least 2 individuals with clinical features of Rett syndrome (PMID 16473305, internal database - GeneDx) (PS4_supporting). 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 16077736, ClinVar, internal database - GeneDx, internal database - Invitae) (PM5_strong). The p.Lys304Glu variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 in vitro binding and transcription repression assays have shown that this variant impacts protein function (PMID 23770565) (PS3_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.Lys304Glu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PS3_supporting, PS4_supporting, PM2_supporting, PP3).
GeneDx	RCV001564211	SCV001787337	pathogenic	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate K304E impacts the binding ability of MECP2 (Lyst et al., 2013); Multiple pathogenic missense variants at this residue (p.K304Q and p.K304T) have been reported in association with Rett syndrome (Charman et al., 2005; Lindy et al., 2018); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28348241, 24970834, 16473305, 23770565)
Centre for Population Genomics, CPG	RCV000133286	SCV004101566	likely pathogenic	Rett syndrome	2023-09-25	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 2.0, this variant is classified as likely pathogenic. At least the following criteria are met: ≥2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact (REVEL score >=0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). Has been observed in in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting).
RettBASE	RCV000133286	SCV000188294	uncertain significance	Rett syndrome	2008-01-21	no assertion criteria provided	curation