Submissions for variant NM_001110792.2(MECP2):c.1225G>A (p.Glu409Lys)

gnomAD frequency: 0.00308  dbSNP: rs56268439

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000202529	SCV002540719	benign	Rett syndrome	2022-05-10	reviewed by expert panel	curation	The allele frequency of the p.Glu397Lys variant in MECP2 (NM_004992) is 0.393% in European (Non-Finnish) 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 p.Glu397Lys variant is observed in at least 2 unaffected individuals (PMID 10577905,12384770, RettBASE) (BS2). In summary, the p.Glu397Lys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2).
Eurofins Ntd Llc (ga)	RCV000081194	SCV000113102	benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000081194	SCV000170232	benign	not specified	2016-07-15	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	RCV000081194	SCV000247940	likely benign	not specified	2017-06-22	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224642	SCV000280649	likely benign	not provided	2014-11-26	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081987	SCV000556742	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224642	SCV000609420	likely benign	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000716944	SCV000847789	benign	History of neurodevelopmental disorder	2014-08-01	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Mendelics	RCV000202529	SCV001142081	benign	Rett syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000081194	SCV001476542	benign	not specified	2020-04-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498425	SCV002807850	likely 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	2022-01-26	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV000202529	SCV004098724	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).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000081194	SCV004847542	benign	not specified	2018-03-19	criteria provided, single submitter	clinical testing	The p.Glu397Lys variant in MECP2 is classified as a benign, because It has been has been identified in 0.39% (328/84800) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP), including 131 hemizygous individuals. While it has been reported in individuals with Rett syndrome and has also been reported in ClinVar (Variant ID 95187). However, in one family a second causative variant was identified in a female proband with Rett, while her her unaffected sister and their hemizygous father also carried the p.Glu397Lys variant (Wan 1999). Computational prediction tools and conservation analysis suggest that the p.Glu397Lys variant may not impact the protein. ACMG/AMP Criteria applied: BS1; BP4_Strong; BP2.
Breakthrough Genomics, Breakthrough Genomics	RCV000224642	SCV005206917	likely benign	not provided		criteria provided, single submitter	not provided
RettBASE	RCV000081194	SCV000187932	benign	not specified	2013-12-05	no assertion criteria provided	curation
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000202529	SCV000257517	uncertain significance	Rett syndrome	2013-09-04	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000224642	SCV000804256	benign	not provided	2015-04-03	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000081194	SCV001743998	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000081194	SCV001928703	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081194	SCV001960130	benign	not specified		no assertion criteria provided	clinical testing