Submissions for variant NM_001110792.2(MECP2):c.1152_1237del (p.His384fs)

dbSNP: rs1557135314

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001383624	SCV001582843	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2022-08-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His372Glnfs*4) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Rett syndrome (PMID: 11269512, 26984561). ClinVar contains an entry for this variant (Variation ID: 156339). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Leu386Glnfs*4) have been determined to be pathogenic (PMID: 17387578, 19914908). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Centre for Population Genomics, CPG	RCV000170135	SCV004098758	pathogenic	Rett syndrome	2023-08-14	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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting). At least one patient with this variant has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PP4, PMID: 17387578). Has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting, RettBase internal database, PMID: 17387578, PMID: 11269512).
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000144423	SCV000189478	not provided	not provided		no assertion provided	not provided
RettBASE	RCV000170135	SCV000222463	pathogenic	Rett syndrome	2007-11-01	no assertion criteria provided	curation