Submissions for variant NM_001110792.2(MECP2):c.1196C>T (p.Pro399Leu)

gnomAD frequency: 0.00010  dbSNP: rs63390262

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001800445	SCV002047342	benign	Rett syndrome	2021-12-13	reviewed by expert panel	curation	The allele frequency of the p.Pro387Leu (NM_004992.3) variant in MECP2 is 0.026% in South 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.Pro387Leu variant is observed in at least 2 unaffected individuals (PMID 12161600, GeneDx internal database) (BS2). In summary, the p.Pro387Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224689	SCV000280687	likely benign	not provided	2015-05-08	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608016	SCV000698534	likely benign	not specified	2017-11-22	criteria provided, single submitter	clinical testing	Variant summary: The MECP2 c.1160C>T (p.Pro387Leu) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 17/186675 control chromosomes (gnomAD) at a frequency of 0.0000911, which is approximately 11 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported via a publication in a homozygous female suspected to have Rett syndrome (Bhanushali_2016), however, her father also carried the variant and was stated to be mentally normal. In addition, one clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as likely benign.
GeneDx	RCV000224689	SCV000728726	likely benign	not provided	2021-04-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 11309367, 16708070, 26755454, 28447035, 29206688)
Invitae	RCV001087050	SCV000766872	benign	Severe neonatal-onset encephalopathy with microcephaly	2023-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371977	SCV002625072	uncertain significance	Inborn genetic diseases	2016-10-10	criteria provided, single submitter	clinical testing	The p.P387L variant (also known as c.1160C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 1160. The proline at codon 387 is replaced by leucine, an amino acid with similar properties. This variant was originally reported in a mentally retarded patient (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6). In addition, this variant was identified in homozygosity in a female with clinical suspicion of Rett syndrome; however, it was also found in her unaffected father (Bhanushali AA et al. J Clin Neurosci, 2016 Mar;25:127-9). This variant was previously reported in the SNPDatabase as rs63390262. In the NHLBI Exome Sequencing Project (ESP), this variant was not observed in 6325 samples with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002498651	SCV002813639	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	2022-01-03	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV001800445	SCV004101588	benign	Rett syndrome	2023-09-25	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 between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2).
PreventionGenetics, part of Exact Sciences	RCV003895003	SCV004712967	likely benign	MECP2-related condition	2022-04-08	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	RCV000132908	SCV000187889	uncertain significance	X-linked intellectual disability-psychosis-macroorchidism syndrome	2002-04-10	no assertion criteria provided	curation