Submissions for variant NM_001110792.2(MECP2):c.6CGC[8] (p.Ala7_Ala8dup)

dbSNP: rs398123566

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000714629	SCV002769737	benign	Rett syndrome	2022-12-08	reviewed by expert panel	curation	The allele frequency of the c.-143_-138dup variant in MECP2 (NM_004992.3) is 0.033% in African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The c.-143_-138dup variant is observed in at least 2 unaffected individuals (PMID: 15367913, internal database) (BS2). The c.-143_-138dup variant has been observed in at least 2 individuals with neurological disorders (PMID: 33880059, 16829352) (PS4 not met). In summary, the c.-143_-138dup variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2).
GeneDx	RCV000144801	SCV000191027	uncertain significance	not provided	2013-07-17	criteria provided, single submitter	clinical testing	The c.23_24insCGCCGC (aka c.18_23dupCGCCGC) variant results in the duplication of two amino acid residues in a poorly conserved region of the MECP2_e1 transcript. This variant has been reported as a benign polymorphism because it was identified in a female with Rett syndrome and her unaffected mother in one family and did not cosegregate with intellectual disability in another family (Evans et al., 2005; Quenard et al., 2006). However, in another study variations in the number of Alanine or Glycine repeats in this region of the protein were found in approximately 1% of females with intellectual disability but a significantly smaller percentage of controls, so the authors suggested these variants may be associated with an increased risk for intellectual disability (Harvey et al., 2007). Internal exome population data indicates this variant has been seen in 2 unaffected males. The variant is found in CHILD-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645135	SCV000766877	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-01-22	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714629	SCV000845341	uncertain significance	Rett syndrome	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000645135	SCV000845342	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2018-08-07	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198685	SCV001369680	benign	Autism, susceptibility to, X-linked 3	2018-09-25	criteria provided, single submitter	clinical testing	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. This variant was detected in hemizygous state.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000170278	SCV002555930	benign	not specified	2022-06-16	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.-143_-138dupCGCCGC (also known as c.18_23dup6 and c.16_21dup) is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00035 in 105710 control chromosomes, including 5 hemizygotes (gnomAD v3.1.2). The observed variant frequency is approximately 42-fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. c.-143_-138dupCGCCGC has been reported in the literature in individuals affected with Rett Syndrome and intellectual disability (examples: Guo_2021, Zahorakova_2016 and Quenard_2006). In these reports, authors have classified the variant as non pathogenic or variant of uncertain significance. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=1) and as benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002408732	SCV002711467	benign	Inborn genetic diseases	2023-12-01	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227687	SCV003924221	benign	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	2022-01-20	criteria provided, single submitter	clinical testing	MECP2 NM_001110792.1 p.Ala7_Ala8dup (c.18_23dup): This variant has been reported in the literature in 2 individuals with Rett syndrome; however, this variant was also present in the unaffected mothers of these individuals. For one case, this variant did not segregate with disease in 1 affected sister (though the sibling's phenotype was reported to be more mild) (Evans 2005 PMID:15367913, Quenard 2006 PMID:16829352). In both published reports, the authors commented that X-inactivation was not skewed and suggested that this variant may not cause disease, but the impact of this variant remained uncertain. This variant is present in 0.05% (28/50882) of European alleles including 2 hemizygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/X-154097642-C-CGCGGCG?dataset=gnomad_r3). This variant is present in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/189763/). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame duplication of 2 Alanine residues at position 7 (within a string of Alanine repeats) and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000144801	SCV004165070	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MECP2: BS2
Centre for Population Genomics, CPG	RCV000714629	SCV004808726	benign	Rett syndrome	2024-02-18	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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1).
RettBASE	RCV000170278	SCV000222610	benign	not specified	2013-06-12	no assertion criteria provided	curation
PreventionGenetics, part of Exact Sciences	RCV004539573	SCV004763930	likely benign	MECP2-related disorder	2021-01-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).