Submissions for variant NM_001110792.2(MECP2):c.941C>T (p.Pro314Leu)

dbSNP: rs61749723

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000133281	SCV002540711	pathogenic	Rett syndrome	2022-06-30	reviewed by expert panel	curation	The c.905C>T p.(Pro302Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro302Leu) variant has been observed in at least 5 individuals with Rett syndrome or severe neonatal encephalopathy (PMID: 10767337, 30377382, 23696494, 11313756, 16473305, 32472557) (PS4, PP4), where it has been reported as a de novo occurrence (biological parentage unconfirmed) in at least 4 of these individuals (PMID: 10767337, 30377382, 23696494, 11313756) (PM6_very strong). The p.(Pro302Leu) variant occurs in the well-characterized transcriptional repression domain (TRD: aa 302-306) of the MECP2 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID: 10814718, 10814719, 10944854, 17387578, 15737703) (PM5). In summary, the c.905C>T p.(Pro302Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_very strong, PS4, PM1, PM5, PP3, PP4, PM2_supporting).
GeneDx	RCV000413239	SCV000490611	pathogenic	not provided	2018-02-14	criteria provided, single submitter	clinical testing	The P302L missense variant in the MECP2 gene has been reported multiple times previously in association with Rett syndrome (Cheadle et al., 2000; RettBASE). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P302L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position predicted to be within the transcriptional repression domain (TRD). Multiple different missense variants at the same residue as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Rett syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000133281	SCV000537170	likely pathogenic	Rett syndrome	2015-06-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000754784	SCV003445287	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2024-04-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 302 of the MECP2 protein (p.Pro302Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett syndrome (PMID: 10767337). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143738). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 80%. This variant disrupts the p.Pro302 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10944854, 15737703, 16225173, 17387578). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Centre for Population Genomics, CPG	RCV000133281	SCV004232210	pathogenic	Rett syndrome	2024-01-09	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: This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in at least an individual with Rett syndrome without confirmation of paternity and maternity (PM6) PMID: 10767337, ClinVar Variation ID: 143738 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4, PP4). (PMID: 16473305 , ClinVar Variation ID: 143738) Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3).
RettBASE	RCV000133281	SCV000188289	uncertain significance	Rett syndrome	2008-01-21	no assertion criteria provided	curation
The Raphael Recanati Genetics Institute, Rabin Medical Center	RCV000754784	SCV000882666	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2018-09-13	no assertion criteria provided	clinical testing