Submissions for variant NM_001110792.2(MECP2):c.1193_1224del (p.Leu398fs)

dbSNP: rs267608585

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001035576	SCV001198909	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu386Argfs*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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Rett syndrome (PMID: 11746022, 12075485, 19914908, 21160487). This variant is also known as c.1157_1188del32 and 1157del32. ClinVar contains an entry for this variant (Variation ID: 143366). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000168702	SCV001430670	pathogenic	Rett syndrome	2020-07-16	criteria provided, single submitter	clinical testing	This MECP2 variant (rs267608585) is absent in a large population dataset and has an entry in ClinVar. This variant has been reported in patients with classic and variant forms of Rett syndrome. This 32-bp deletion results in a frameshift that is predicted to lead to a premature stop codon (PTC) in the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. This variant is located within a hotspot of deletions in the C-terminus of the MeCP2 protein, which represent ~12% of disease-associated variants in MECP2. We consider it to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168702	SCV001554524	pathogenic	Rett syndrome	2021-03-16	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.1157_1188del32 (p.Leu386ArgfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 173875 control chromosomes (gnomAD). c.1157_1188del32 has been reported in the literature in individuals affected with Rett Syndrome (e.g. Zappella_2001, Kammoun_2004, Philippe_2006, Hadzsiev_2011). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003326356	SCV004033337	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	MECP2: PS2, PVS1:Strong, PM2
RettBASE	RCV000168702	SCV000187872	pathogenic	Rett syndrome	2011-11-01	no assertion criteria provided	curation