Submissions for variant NM_001110792.2(MECP2):c.143_149del (p.Lys48fs)

dbSNP: rs267608424

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000132849	SCV001362257	likely pathogenic	Rett syndrome	2019-06-10	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.107_113delAAGAAGA (p.Lys36ArgfsX87) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182010 control chromosomes (gnomAD). c.107_113delAAGAAGA has been reported in the literature in an individual affected with Rett Syndrome (Philippe_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515925	SCV003444006	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2022-06-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys36Argfs*87) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 451 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 individual(s) with clinical features of MECP2-related conditions (PMID: 16473305). ClinVar contains an entry for this variant (Variation ID: 143324). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg168*) have been determined to be pathogenic (PMID: 10577905, 11058114, 23270700, 24283265, 24511209). 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	RCV000132849	SCV004101589	likely pathogenic	Rett syndrome	2023-10-12	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 likely 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).
RettBASE	RCV000132849	SCV000187828	pathogenic	Rett syndrome	2008-01-21	no assertion criteria provided	curation