Submissions for variant NM_001110792.2(MECP2):c.379C>T (p.Arg127Cys)

dbSNP: rs267608388

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001800452	SCV002047366	uncertain significance	Rett syndrome	2023-08-28	reviewed by expert panel	curation	The p.Arg115Cys (NM_004992.4) in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome; however, this individual was also heterozygous for a de novo truncating variant in MECP2 (PMID 18652533). The p.Arg115Cys variant (NM_004992.4) occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg115Cys variant (NM_004992.4) in MECP2 is absent from gnomAD (PM2_supporting). The p.Arg115Cys variant (NM_004992.4) is observed in at least 2 unaffected individuals (internal databases) (BS2). In summary, the p.Arg115Cys variant in MECP2 (NM_004992.4) is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, BS2).
GeneDx	RCV000133074	SCV000191034	likely pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	Observed as an apparently de novo variant in a female with classic Rett syndrome in published literature; however, another apparently de novo variant in MECP2 was also identified (Bunyan et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10577905, 22561697, 20631224, 21575601, 34426522, 21831886, 12843318, 32653844, 18652533)
Ambry Genetics	RCV000715718	SCV000846549	uncertain significance	History of neurodevelopmental disorder	2016-05-03	criteria provided, single submitter	clinical testing	The p.R115C variant (also known as c.343C>T), located in coding exon 2 of the MECP2 gene, results from a C to T substitution at nucleotide position 343. The arginine at codon 115 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified asde novo in a female individual with classic Rettsyndrome who also carrieda de novoframeshiftmutation in MECP2. The phase of the two alterations was not confirmed and there was no evidence of skewed x-inactivation (Bunyan DJ, Genet. Test. 2008 Sep; 12(3):373-5).This variant was previously reported in the SNPDatabase as rs267608388, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases.This amino acid position is highly 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,theclinical significance of this variantremains unclear.
Invitae	RCV002514765	SCV003445290	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2023-04-17	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 18652533). 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. 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: 143541). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the MECP2 protein (p.Arg115Cys).
RettBASE	RCV000133074	SCV000188062	not provided	not provided		no assertion provided	not provided