Submissions for variant NM_001110792.2(MECP2):c.1169C>T (p.Ala390Val)

dbSNP: rs201314910

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV002260616	SCV002540677	benign	Rett syndrome	2022-05-10	reviewed by expert panel	curation	The allele frequency of the p.Ala378Val (NM_004992) variant in MECP2 is 0.014% in East Asian sub population in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala378Val variant is observed in at least 2 unaffected individuals (PMID 15737703)(BS2). In summary, the p.Ala378Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2).
Eurofins Ntd Llc (ga)	RCV000132866	SCV000230271	benign	not specified	2014-12-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001090499	SCV000728724	likely benign	not provided	2021-02-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15737703)
Invitae	RCV000694069	SCV000822496	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2023-11-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090499	SCV001246084	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000132866	SCV001362155	likely benign	not specified	2019-05-31	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.1133C>T (p.Ala378Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 175188 control chromosomes (2 hemizygotes). The observed variant frequency is approximately 7 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.1133C>T has been reported in the literature in one female individual affected with Rett Syndrome and patient's unaffected father (Fukuda_2005). This report suggests the variant does not associate with Rett Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Centre for Population Genomics, CPG	RCV002260616	SCV004098723	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).
PreventionGenetics, part of Exact Sciences	RCV003965077	SCV004781358	likely benign	MECP2-related condition	2022-09-11	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).
RettBASE	RCV000132866	SCV000187846	benign	not specified	2010-03-10	no assertion criteria provided	curation