Submissions for variant NM_001110792.2(MECP2):c.1176G>A (p.Val392=)

gnomAD frequency: 0.00015  dbSNP: rs201711454

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	RCV001507043	SCV001711992	benign	Rett syndrome	2021-03-26	reviewed by expert panel	curation	The allele frequency of the p.Val380= variant in MECP2 is 0.018% in Latino sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Val380= variant is observed in at least 2 unaffected individuals (internal database) (BS2). The silent p.Val380= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Val380= variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2, BP7).
GeneDx	RCV000194285	SCV000170231	likely benign	not specified	2017-10-24	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.
Genetic Services Laboratory, University of Chicago	RCV000194285	SCV000247928	likely benign	not specified	2017-06-22	criteria provided, single submitter	clinical testing
Invitae	RCV001088580	SCV000766880	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194285	SCV000917620	benign	not specified	2018-07-06	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.1140G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no effect on splicing. The variant allele was found at a frequency of 6.5e-05 in 169949 control chromosomes, including 4 hemizygotes. The observed variant frequency is approximately 8-fold above 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.1140G>A in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000645138	SCV001156230	likely benign	not provided	2018-07-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945133	SCV004764048	likely benign	MECP2-related condition	2019-11-21	criteria provided, single submitter	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).