Submissions for variant NM_001110792.2(MECP2):c.1001C>T (p.Pro334Leu)

dbSNP: rs61751450

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000133300	SCV002569943	pathogenic	Rett syndrome	2022-07-05	reviewed by expert panel	curation	The c.965C>T p.(Pro322Leu) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Pro322Leu) variant has been observed in at least 5 individuals with Rett syndrome (PMID: 10814718, 19722030, 17089071, 16672765, 11402105, 16473305) (PS4, PP4), where it has been reported in as de novo occurrences (biological parentage unconfirmed) in at least 2 individuals (PMID 10814718, 11402105) (PM6_strong). Multiple missense variants have been previously identified within this codon, at least one of which is classified as pathogenic; this indicates that this residue is critical to the function of the protein (PMID 10814719, 16966553, 16225173, 32820509) (PM5). In summary, the c.965C>T p.(Pro322Leu) variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM6_strong, PP4, PM5).
GeneDx	RCV000414666	SCV000491070	pathogenic	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The P322L pathogenic variant in the MECP2 gene is a recurrent variant reported in cohorts of individuals diagnosed with Rett syndrome (Lima et al., 2009; Kim et al., 2006; Philippe et al., 2006; Hoffbuhr et al., 2001) and has been reported specifically in a female who exhibited severe Rett syndrome clinical features (Huppke et al., 2000). The P322L variant 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 P322L 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 position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001849960	SCV002245479	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2021-05-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 322 of the MECP2 protein (p.Pro322Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Rett syndrome (PMID: 17089071, 15526954, 10814718). ClinVar contains an entry for this variant (Variation ID: 143754). Experimental studies have shown that this variant affects MECP2 protein function (PMID: 29718204). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Lab, CHRU Brest	RCV003883134	SCV004697678	likely pathogenic	Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome; Autism, susceptibility to, X-linked 3		criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV000133300	SCV004808975	pathogenic	Rett syndrome	2024-03-08	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 has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). (PMID: 17089071, PMID 10814718, 11402105) Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 35010767, 35712450, 17089071, 16473305, 15526954, 34126956, 10814718, 12075494, 24623853, 26457613, 19194883, 16672765, 32370253,ClinVar Variation ID: 143754) This variant is absent from gnomAD (PM2_Supporting).
RettBASE	RCV000133300	SCV000188309	uncertain significance	Rett syndrome	2010-08-24	no assertion criteria provided	curation