Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
New York Genome Center | RCV002274929 | SCV002564262 | uncertain significance | Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome | 2021-10-08 | criteria provided, single submitter | clinical testing | The hemizygous c.872C>T (p.Ala291Val) variant identified in the MECP2 gene is the substitution of a moderately conserved Alanine for Valine at amino acid 291/499 (exon 3/3) in transcript NM_001110792.2. MECP2 is alternatively spliced, and this variant is also called c.836C>T (p.Ala279Val) when annotated from transcript NM_004992.3 (NP_004983.1). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.127) and Benign (REVEL; score:0.492) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:143710) and has been identified in three affected individuals in a single publication in the literature [PMID:15526954]. The p.Ala291 residue is within the second Transcription Repression Domain (TRD) of MECP2 (UniProtKB:P51608; PMID:28544139), where other pathogenic missense variants have been identified [PMID:28544139]. The hemizygous c.872C>T (p.Ala291Val) variant identified in the MECP2 gene is reported as a Variant of Uncertain Significance. |
Invitae | RCV003522937 | SCV004299166 | likely pathogenic | Severe neonatal-onset encephalopathy with microcephaly | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the MECP2 protein (p.Ala279Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 15526954). ClinVar contains an entry for this variant (Variation ID: 143710). 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 not expected to disrupt MECP2 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Rett |
RCV000133252 | SCV000188256 | uncertain significance | Rett syndrome | 2007-12-03 | no assertion criteria provided | curation |