Submissions for variant NM_001110792.2(MECP2):c.-31AG[2]

dbSNP: rs587783128

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	RCV002260622	SCV002540698	benign	Rett syndrome	2022-02-18	reviewed by expert panel	curation	The allele frequency of the c.-187_-186del variant in MECP2 (NM_004992.3) is 0.058% in European (non-Finnish) sub population and 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). In summary, the c.-187_-186del variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1).
GeneDx	RCV000144799	SCV000191024	likely benign	not specified	2017-11-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000144799	SCV001362256	benign	not specified	2019-05-17	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.-187_-186delAG is located in the untranslated mRNA region upstream of the initiation codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 44218 control chromosomes (gnomAD). The observed variant frequency is approximately 30 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. To our knowledge, no occurrence of c.-187_-186delAG in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV001522613	SCV001732188	benign	Severe neonatal-onset encephalopathy with microcephaly	2022-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000144799	SCV002066933	likely benign	not specified	2017-11-08	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV002260622	SCV004098713	benign	Rett syndrome	2023-08-14	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 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 2.0 (BA1).
RettBASE	RCV000170283	SCV000222615	uncertain significance	X-linked intellectual disability-psychosis-macroorchidism syndrome	2007-11-01	no assertion criteria provided	curation