Submissions for variant NM_001110792.2(MECP2):c.508A>G (p.Thr170Ala)

dbSNP: rs61748411

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000133128	SCV002047358	pathogenic	Rett syndrome	2021-10-26	reviewed by expert panel	curation	The p.Thr158Ala variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with preserved speech variant Rett syndrome (PMID 11269512) (PM6). The p.Thr158Ala variant has been observed in 2 other individuals with Rett syndrome (PMID 18842453, 15057977) (PS4_moderate, PP4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 18337588, 23270700, 23421866, 10508514, internal database - Invitae) (PM5_strong). The p.Thr158Ala variant in MECP2 is absent from gnomAD (PM2_supporting). Heterochromatin binding and in vitro transcription repression assays have shown that this variant impacts protein function (PMID 12843318) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Thr158Ala variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PM6, PS4_moderate, PS3_supporting, PM2_supporting, PP3, PP4).
GeneDx	RCV000482544	SCV000567941	pathogenic	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The T158A missense variant has been previously reported as a de novo variant in a female patient with the preserved speech variant of Rett syndrome (Vacca et al., 2001). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T158A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position predicted to be within the methyl-binding domain of the MECP2 protein, and a missense variant in the same codon (T158M) as well as multiple missense pathogenic variants in nearby residues have been reported in association with Rett syndrome (RettBASE; Stenson et al., 2014), supporting the functional importance of this region of the protein. Multiple functional studies suggest that T158A impairs normal protein function (Kudo et al., 2003; Agarwal et al., 2011). Therefore, we interpret T158A as a pathogenic variant.
Invitae	RCV003522933	SCV004299171	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-03-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 158 of the MECP2 protein (p.Thr158Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr158 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10508514, 18337588, 23421866, 26647311). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MECP2 function (PMID: 22119903, 26418480). 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) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. ClinVar contains an entry for this variant (Variation ID: 143590). This missense change has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 11269512). In at least one individual the variant was observed to be de novo.
RettBASE	RCV000133128	SCV000188120	uncertain significance	Rett syndrome	2004-08-06	no assertion criteria provided	curation