Submissions for variant NM_001110792.2(MECP2):c.1191_1236del (p.Leu398fs)

dbSNP: rs267608329

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479970	SCV000571773	pathogenic	not provided	2023-03-26	criteria provided, single submitter	clinical testing	Identified in two unrelated females with Rett syndrome; however, in both published cases the c.1155_1200del46 variant was likely part of a complex allele, as one of the patients also harbored an in-frame insertion/deletion while the other had a second frameshift variant in MECP2 (Lee et al., 2001; Weaving et al., 2003); Also reported as an isolated pathogenic variant in two unrelated females in RettBASE; however, no additional information is available regarding the phenotype or family history (Christodoulou et al., 2003); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12655490, 16473305, 19914908, 12872250, 11738860)
Invitae	RCV001387825	SCV001588545	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu386Alafs*8) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acid(s) of the MECP2 protein. This variant is present in population databases (rs267608329, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with clinical features of Rett syndrome (PMID: 16473305, 19914908). This variant is also known as c.1152_1197del. ClinVar contains an entry for this variant (Variation ID: 143360). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Pro389*) have been determined to be pathogenic (PMID: 17089071, 17387578, 19914908, 20151026, 21982064). 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.
Baylor Genetics	RCV003333027	SCV004041345	pathogenic	Syndromic X-linked intellectual disability Lubs type	2023-08-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000479970	SCV004184957	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MECP2: PVS1, PM2:Supporting
Centre for Population Genomics, CPG	RCV000132886	SCV004232269	pathogenic	Rett syndrome	2024-01-10	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 3.0, 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). ClinVar Variation ID: 143360, PMID: 23696494, 12180070 , 16473305 This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID 23696494 This variant is absent from gnomAD (PM2_Supporting).
RettBASE	RCV000132886	SCV000187866	pathogenic	Rett syndrome	2008-01-21	no assertion criteria provided	curation