ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.491C>G (p.Pro164Arg) (rs61748404)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics Laboratory,Children's Mercy Hospital and Clinics RCV000133116 SCV000223855 pathogenic Rett syndrome criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000133116 SCV000247968 pathogenic Rett syndrome 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000254929 SCV000321874 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing The P152R pathogenic variant in the MECP2 gene has been identified in patients with both classic and atypical Rett syndrome (Cheadle et al., 2000; Sheen et al., 2013; Kharrat et al., 2016; RettBase). Additionally, P152R has been observed as a de novo variant with confirmed parentage in a patient with global developmental delay, hypotonia, muscle weakness, and abnormal EEG previously tested at GeneDx. Several functional studies have shown that P152R has a damaging effect by severely affecting heterochromatin clustering and repressing transcription (Agarwal et al., 2011; Casas-Delucchi et al., 2012; Kudo et al., 2013). Another study using in silico and in vitro approaches demonstrated that P152R had a significant destabilizing effect on the protein (Kucukkal et al., 2015). The P152R mutation is a non-conservative amino acid substitution, which alters a highly conserved position within the predicted methyl-binding domain of the MECP2 protein. The P152R variant is not observed in large population cohorts (Lek et al., 2016). Additionally, different missense changes at this residue (P152A, P152H) have been reported as pathogenic in the published literature in association with autism and Rett syndrome, respectively (Stenson et al., 2014). Therefore, P152A is interpreted to be a pathogenic variant.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000445575 SCV000537192 uncertain significance not specified 2015-07-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000133116 SCV000919622 pathogenic Rett syndrome 2018-10-15 criteria provided, single submitter clinical testing Variant summary: MECP2 c.455C>G (p.Pro152Arg) results in a non-conservative amino acid change located in the methyl-CpG DNA binding domain (IPR001739) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 177980 control chromosomes (gnomAD). The variant, c.455C>G, has been reported in the literature in multiple individuals affected with Rett Syndrome, Classic (e.g. Cheadle 2000, Obata 2000, Huppke 2000, Philippe 2006, Buoni 2008). These data indicate that the variant is very likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, demonstrating a disrupted heterochromatin binding for the variant protein (e.g. Adegbola 2009, Sheikh 2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classified as pathogenic, the other VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000801154 SCV000940920 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 152 of the MECP2 protein (p.Pro152Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with classic Rett syndrome (PMID: 10767337) and in individuals affected with typical and atypical Rett syndrome (PMID:11241840, 11055898, 10814718, 23859859, 15173251). ClinVar contains an entry for this variant (Variation ID: 143579). Experimental studies have shown that this missense change showed a significant increase in the number of chromocenters, significantly higher recovery rates than wild type MeCP2, was highly destabilizing, and severely affected the heterochromatin clustering (PMID: 26418480, 22923521, 21831886, 27929079). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000445575 SCV001156681 pathogenic not specified 2018-10-09 criteria provided, single submitter clinical testing The MECP2 c.455C>G; p.Pro152Arg variant (rs61748404) is reported in the literature in numerous individuals affected with Rett syndrome (Cheadle 2000, Maortua 2013, Sheen 2013, Rettbase) and has been reported to occur de novo (Cheadle 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 143579), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant at this codon (p.Arg152His) has been reported in an individual with Rett syndrome and is considered pathogenic (Sheikh 2016). The proline at codon 152 is highly conserved, and structural modeling suggests that the p.Pro152Arg variant disrupts local hydrogen bonding patterns (Kucukkal 2015). Further, biochemical analyses demonstrate that this variant destabilizes MECP2 protein (Kucukkal 2015), while expression of the p.Pro152Arg variant in cultured cells alters nuclear heterochromatin organization (Agarwal 2011, Casas-Delucchi 2012, Sheikh 2016). Based on available information, this variant is considered to be pathogenic. References: Link to Rettbase: https://www.rettsyndrome.org/ Agarwal N et al. MeCP2 Rett mutations affect large scale chromatin organization. Hum Mol Genet. 2011 Nov 1;20(21):4187-95. Casas-Delucchi CS et al. Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re-establishes higher order chromatin organization. Nucleic Acids Res. 2012 Dec;40(22):e176. Cheadle JP et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet. 2000 Apr 12;9(7):1119-29. Kucukkal TG et al. Impact of Rett Syndrome Mutations on MeCP2 MBD Stability. Biochemistry. 2015 Oct 20;54(41):6357-68. Maortua H et al. MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males). J Mol Diagn. 2013 Sep;15(5):723-9. Sheen V et al. Atypical features in MECP2 P152R-associated Rett syndrome. Pediatr Neurol. 2013 Aug;49(2):124-6. Sheikh TI et al. From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2. Sci Rep. 2016 Dec 8;6:38590.
RettBASE RCV000133116 SCV000188107 pathogenic Rett syndrome 2013-12-05 no assertion criteria provided curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000133116 SCV000804882 pathogenic Rett syndrome 2011-10-29 no assertion criteria provided clinical testing

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