Submissions for variant NM_001110792.2(MECP2):c.504C>G (p.Asp168Glu)

dbSNP: rs61748408

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081204	SCV000191037	pathogenic	not provided	2022-08-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the D156E variant results in impaired heterochromatin binding, reduced transcriptional repression, and destabilization of the MeCP2 protein (Kudo et al., 2003; Kucukkal et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19722030, 26418480, 29655203, 32472557, 10805343, 21831886, 12843318, 26984561, 12075485, 11524741)
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000169946	SCV000223858	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000081204	SCV000230259	pathogenic	not provided	2013-01-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000169946	SCV000247969	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000815972	SCV000956455	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 156 of the MECP2 protein (p.Asp156Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 11524741, 12075485, 15737703, 16473305, 16672765, 19722030, 22182064, 26984561, 27354166). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 95196). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. Experimental studies have shown that this missense change affects MECP2 function (PMID: 12843318, 26418480). This variant disrupts the p.Asp156 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been observed in individuals with MECP2-related conditions (PMID: 11309679, 15737703, 18021529, 22182064), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Suma Genomics	RCV000169946	SCV001847692	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000169946	SCV002526736	pathogenic	Rett syndrome	2022-06-01	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS4, PS2_MOD, PS1_MOD, PM1, PM5, PM2_SUP, PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000169946	SCV002601737	pathogenic	Rett syndrome	2022-11-17	criteria provided, single submitter	clinical testing
RettBASE	RCV000169946	SCV000188113	pathogenic	Rett syndrome	2016-04-26	no assertion criteria provided	research