Submissions for variant NM_001110792.2(MECP2):c.1375G>A (p.Ala459Thr)

gnomAD frequency: 0.00009  dbSNP: rs267608626

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	RCV001800447	SCV002047340	benign	Rett syndrome	2021-12-13	reviewed by expert panel	curation	The allele frequency of the p.Ala447Thr (NM_004992.3) variant in MECP2 is 0.02% in East Asian 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.Ala447Thr variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). In summary, the p.Ala447Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088957	SCV000556730	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000678237	SCV001815276	likely benign	not provided	2021-05-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23810759, 30564305)
Ambry Genetics	RCV002381448	SCV002692307	likely benign	Inborn genetic diseases	2018-03-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CeGaT Center for Human Genetics Tuebingen	RCV000678237	SCV004701566	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MECP2: BP4, BS2
Centre for Population Genomics, CPG	RCV001800447	SCV004808997	benign	Rett syndrome	2024-03-13	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	RCV000132993	SCV000187979	benign	not specified	2013-12-05	no assertion criteria provided	curation
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000678237	SCV000804260	uncertain significance	not provided	2015-04-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544311	SCV004761074	likely benign	MECP2-related disorder	2022-05-26	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).