Submissions for variant NM_001110792.2(MECP2):c.490C>G (p.Pro164Ala)

gnomAD frequency: 0.00002  dbSNP: rs179363900

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000991003	SCV001711999	likely pathogenic	Rett syndrome	2021-03-26	reviewed by expert panel	curation	Functional studies have shown that this variant shows partial reduction in heterochromatin binding (PMID 18989701) (PS3_supporting). The variant has been reported to segregate in three informative meioses (PMID 18989701, internal database) (PP1_Moderate). The p.Pro152Ala variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). A pathogenic missense variant (p.Pro152Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (10767337) (PM5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Pro152Ala variant in MECP2 is classified as likely pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS3_supporting, PP1_moderate, PM1, PM5, PP3).
GeneDx	RCV000492792	SCV000582724	uncertain significance	not provided	2020-05-28	criteria provided, single submitter	clinical testing	Reported in a female with pervasive developmental disorder, obesity, abnormal EEG, and inherited from her father with learning disabilities and obesity (Adegbola et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27929079, 29655203, 26842955, 18989701, 33258288)
Fulgent Genetics, Fulgent Genetics	RCV000763200	SCV000893819	pathogenic	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	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000991003	SCV001142091	likely pathogenic	Rett syndrome	2023-12-21	criteria provided, single submitter	clinical testing	Other patients with the same variant not presenting phenotype.
Invitae	RCV001246099	SCV001419437	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 152 of the MECP2 protein (p.Pro152Ala). This variant is present in population databases (rs179363900, gnomAD no frequency). This missense change has been observed in individual(s) with mild forms of Rett syndrome (PMID: 18989701, 27929079, 29655203). ClinVar contains an entry for this variant (Variation ID: 11844). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 18989701, 26842955, 27929079). This variant disrupts the p.Pro152 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767337, 11241840, 27929079). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000133115	SCV001442525	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2020-10-14	criteria provided, single submitter	research	ACMG codes:PS3; PS4M; PM1; PM2; PM5; PP4
Baylor Genetics	RCV001246099	SCV001523356	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2019-05-31	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000492792	SCV002017251	pathogenic	not provided	2020-11-24	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV000991003	SCV004098714	likely pathogenic	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 likely pathogenic. At least the following criteria are met: Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3, PMID: 18989701). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Another missense variant (c.491C>G, p.Pro164Arg, ClinVar Variation ID: 143579) in the same codon has been classified as pathogenic for Rett syndrome by the ClinGen Rett and Angelman-like Disorders Expert Panel (PM5). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3).
OMIM	RCV000012618	SCV000032853	pathogenic	Rett syndrome, zappella variant	2009-01-01	no assertion criteria provided	literature only
RettBASE	RCV000133115	SCV000188106	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2009-03-04	no assertion criteria provided	curation