Submissions for variant NM_001110792.2(MECP2):c.746del (p.Gly249fs)

dbSNP: rs61749743

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012620	SCV000282495	pathogenic	Rett syndrome	2016-01-18	criteria provided, single submitter	clinical testing	This frameshift variant alters amino acid position 237 leading to premature termination codon 10 amino acids downstream. Variant is absent from large and broad cohorts of the ExAC project while it has been reported in at least seven RTT patients. Functional studies have shown the variant to alter the expression levels of several proteins, however the clinical relevance of these altered expressions are uncertain. Reputable databases list variant as “Pathogenic”. Considering all evidence, the variant was classified as Deleterious Variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506656	SCV000604151	pathogenic	not specified	2017-03-24	criteria provided, single submitter	clinical testing
Invitae	RCV001045878	SCV001209752	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2022-07-12	criteria provided, single submitter	clinical testing	This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Gly255*) have been determined to be pathogenic (PMID: 1241840, 10508514, 17089071, 23270700). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 11846). This variant is also known as 706delG. This premature translational stop signal has been observed in individual(s) with Rett Syndrome (PMID: 10805343, 18842453, 19724012). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly237Valfs*11) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 250 amino acid(s) of the MECP2 protein.
Ambry Genetics	RCV002362579	SCV002664234	pathogenic	Inborn genetic diseases	2017-09-08	criteria provided, single submitter	clinical testing	The c.710delG pathogenic mutation, located in coding exon 3 of the MECP2 gene, results from a deletion of one nucleotide at nucleotide position 710, causing a translational frameshift with a predicted alternate stop codon (p.G237Vfs*11). This mutation has been detected in several individuals with diagnoses of Rett syndrome (Laccone F et al. Hum. Mutat., 2001 Mar;17:183-90; Buoni S et al. Clin Neurophysiol, 2008 Nov;119:2455-8; Freilinger M et al. Dev Med Child Neurol, 2010 Oct;52:962-5; Zhang J et al. Clin. Genet., 2012 Dec;82:526-33; Hadzsiev K et al. J. Hum. Genet., 2011 Mar;56:183-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Centre for Population Genomics, CPG	RCV000012620	SCV004098832	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). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4, RettBase internal database, PMID: 21160487, PMID: 11241840). This variant is absent from gnomAD (PM2_Supporting).
OMIM	RCV000012620	SCV000032855	pathogenic	Rett syndrome	2009-09-01	no assertion criteria provided	literature only
RettBASE	RCV000012620	SCV000188205	pathogenic	Rett syndrome	2011-11-01	no assertion criteria provided	curation