rs28934906

Description

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011811, PMID:10508514). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143590, PMID:11269512). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.945>=0.6, 3CNET: 0.995>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The p.T158M pathogenic mutation (also known as c.473C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 473. The threonine at codon 158 is replaced by methionine, an amino acid with similar properties. As one of the most common Rett syndrome mutations, this mutation accounts for 10-13% of MECP2 mutations and has been seen in many individuals with classic Rett syndrome as well as in mildly affected individuals with preserved speech (Amir RE, et al. Nat. Genet. 1999;23(2):185-8.; Archer HL, et al. J. Med. Genet. 2006;43(5):451-6; Bebbington A, et al. J. Med. Genet. 2010;47(4):242-8; Archer H et al. J. Med. Genet., 2007 Feb;44:148-52; Huppke P et al. Hum. Mol. Genet., 2000 May;9:1369-75; The Deciphering Developmental Disorders Study. Nature. 2017 02;542(7642):433-438.; Guo H et al. Mol. Autism. 2018 Dec;9:64.; Tsang MH et al. Epilepsia Open. 2019 Mar;4(1):63-72.). This mutation has been documented in severely affected males, as well as in unaffected females with confirmed skewed X-chromosome inactivation that favors the expression of the normal allele (Villard L, et al. Neurology 2000;55(8):1188-93). In one study, in vitro functional analyses indicated that this mutation had intermediate affinity to heterochromatin and moderate effects on transcriptional repressive activity (Kudo S, J. et al. Med. Genet. 2003;40(7):487-93). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Recurrent missense substitution that accounts for 9-12% of MECP2 pathogenic variants and has been identified in females with both classic and atypical Rett syndrome (Percy et al., 2007; Neul et al., 2008; Bao et al., 2013; RettBASE); Also identified in males with severe neonatal-onset encephalopathy and in females who did not meet clinical criteria for Rett syndrome but had overlapping clinical features, including pervasive developmental disorder or clinical features suggestive of Angelman syndrome (Suter et al., 2014; Kleefstra et al., 2005; Villard et al., 2000); In vitro functional studies indicate that T158M impairs normal protein function (Yusufzai et al., 2000; Kudo et al., 2003; Agarwal et al., 2011; Lyst et al., 2013; Sheikh et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31031587, 12030010, 12843318, 21831886, 11071498, 28920956, 31535341, 31095231, 30945278, 30868116, 29655203, 30564305, 26175308, 28135719, 17236109, 17881312, 16077729, 25533962, 23921973, 12719401, 26418480, 26647311, 26795593, 23770565, 11058114, 10508514, 18337588, 18174548, 23421866, 14560307, 24511209, 23270700, 19442733, 19217433, 11738866, 11392517, 11738879, 10852707, 27929079)

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

The missense variant p.T158M in MECP2 (NM_004992.3) has been reported in multiple patients with Rett syndrome (Das DK et al; Brown K et al).It is the most common mutation in the Rett database.Functional studies have shown a damaging effect (Agarwal N et al). The variant has been submitted to ClinVar as Pathogenic. The p.T158M variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T158M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 158 of MECP2 is conserved in all mammalian species. The nucleotide c.473 in MECP2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

The MECP2 c.473C>T; p.Thr158Met variant (rs28934906), is reported in the literature in multiple individuals affected with classical Rett syndrome (see link to RettBASE and references therein). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 11811), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 158 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Thr158Met variant is considered to be pathogenic. References: Link to RettBASE (http://mecp2.chw.edu.au/cgi-bin/mecp2/search/process-search.cgi)

This sequence change replaces threonine with methionine at codon 158 of the MECP2 protein (p.Thr158Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Rett syndrome and is considered one of the most common causes of the condition (PMID: 10508514, 18337588, 23421866, 26647311; RettBASE). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11811). 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. Experimental studies have shown that this missense change affects MECP2 protein function (PMID: 10852707, 11058114, 11738866, 12843318, 21831886, 26647311). For these reasons, this variant has been classified as Pathogenic.