Submissions for variant NM_001110792.2(MECP2):c.785G>A (p.Arg262His)

dbSNP: rs61750227

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001800456	SCV002047355	uncertain significance	Rett syndrome	2021-10-26	reviewed by expert panel	curation	The p.Arg250His variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (RettBASE, internal database - GeneDx) (BS2). The p.Arg250His variant in MECP2 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools are inconclusive for this variant (no criteria met). In summary, the p.Arg250His variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PM2_supporting).
Ambry Genetics	RCV000721068	SCV000851953	uncertain significance	History of neurodevelopmental disorder	2013-04-30	criteria provided, single submitter	clinical testing	​The p.R250H variant (also known as c.749G>A) is located in coding exon 3 of the MECP2 gene. This variant results from a G to A substitution at nucleotide position 749. The arginine at codon 250 is replaced by histitine, an amino acid with very similar properties. This variant was previously reported in the SNPDatabase as rs61750227. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is not conserved well conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging by PolyPhen and deleterious SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae	RCV001231150	SCV001403659	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 250 of the MECP2 protein (p.Arg250His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 143679). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001588992	SCV001825187	likely benign	not provided	2019-08-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001588992	SCV003810865	uncertain significance	not provided	2021-11-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390828	SCV004121242	uncertain significance	MECP2-related condition	2022-10-24	criteria provided, single submitter	clinical testing	The MECP2 c.749G>A variant is predicted to result in the amino acid substitution p.Arg250His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. However, this variant was documented in two apparently unaffected individuals in RettBASE (http://mecp2.chw.edu.au/cgi-bin/mecp2/search/process-search.cgi). Two different missense variants affecting the same residue have been reported in association with Rett or Rett-like syndrome in the literature (see, Zhang et al. 2019. PubMed ID: 30405208, Table S7). This variant is classified as 'uncertain' by a ClinGen expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/143679/). Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
RettBASE	RCV000133221	SCV000188220	benign	not specified	2004-06-17	no assertion criteria provided	curation