Submissions for variant NM_001110792.2(MECP2):c.953G>A (p.Arg318His)

dbSNP: rs61751443

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000133290	SCV000248006	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000256087	SCV000322254	pathogenic	not provided	2021-03-30	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate that the p.R306H variant abolishes binding of MECP2 to DNA (Heckman et al., 2014); This variant is associated with the following publications: (PMID: 31780880, 11055898, 12655490, 11214906, 15057977, 16473305, 24970834, 10767337, 23921973)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000133290	SCV000537171	likely pathogenic	Rett syndrome	2015-06-30	criteria provided, single submitter	clinical testing
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000133290	SCV000693793	likely pathogenic	Rett syndrome	2018-01-01	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001778753	SCV002016294	pathogenic	Neurodevelopmental disorder	2021-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV001857484	SCV002120295	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2022-12-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg306 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10991688, 14649554, 16473305, 23770565, 24511209, 24970834). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 143746). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337, 23921973). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 306 of the MECP2 protein (p.Arg306His).
Centre for Population Genomics, CPG	RCV000133290	SCV004232314	pathogenic	Rett syndrome	2023-12-06	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 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).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).(PubMed: 11055898‚ 15057977‚ 16473305, 10767337, 23921973 ClinVar database Variation ID: 143746)
RettBASE	RCV000133290	SCV000188299	pathogenic	Rett syndrome	2011-02-15	no assertion criteria provided	curation
Laboratory of Medical Genetics, University of Torino	RCV000133290	SCV002583294	pathogenic	Rett syndrome	2022-10-09	no assertion criteria provided	research