ClinVar Miner

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

dbSNP: rs61750227
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Total submissions: 8
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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 RCV004532612 SCV004121242 uncertain significance MECP2-related disorder 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.
Centre for Population Genomics, CPG RCV001800456 SCV004808876 likely benign Rett syndrome 2024-03-22 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 likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). (RettBASE 1852, 1853, ClinVar Variation ID: 143679)
RettBASE RCV000133221 SCV000188220 benign not specified 2004-06-17 no assertion criteria provided curation

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