Submissions for variant NM_001110792.2(MECP2):c.419A>C (p.Gln140Pro)

dbSNP: rs61748383

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002362775	SCV002626023	likely pathogenic	Inborn genetic diseases	2017-10-26	criteria provided, single submitter	clinical testing	The p.Q128P variant (also known as c.383A>C), located in coding exon 3 of the MECP2 gene, results from an A to C substitution at nucleotide position 383. The glutamine at codon 128 is replaced by proline, an amino acid with similar properties. This alteration has been detected as a de novo occurrence twice: once in a female with later onset regression variant Rett syndrome and once in a female with atypical Rett syndrome without a regression period (Smeets E et al. Am. J. Med. Genet. A, 2003 Oct;122A:227-33; Giampietro PF et al. Childs Nerv Syst, 2006 Mar;22:320-4). In addition, this alteration is located in the Methyl-CpG DNA binding domain and is directly involved in binding interactions (Ramage R et al. Biochem. J., 1994 Apr;299 ( Pt 1):151-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Centre for Population Genomics, CPG	RCV000133087	SCV004232270	likely pathogenic	Rett syndrome	2023-11-09	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 2.0, this variant is classified as likely pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in >=2 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_strong, PMID: 12966523, 15875198). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score >= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
Invitae	RCV003522931	SCV004299174	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 128 of the MECP2 protein (p.Gln128Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett Syndrome (PMID: 12966523, 15875198). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143554). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
RettBASE	RCV000133087	SCV000188076	uncertain significance	Rett syndrome	2007-11-15	no assertion criteria provided	curation