Submissions for variant NM_001110792.2(MECP2):c.1291C>T (p.Pro431Ser)

gnomAD frequency: 0.00003  dbSNP: rs140258520

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	RCV002260619	SCV002540683	benign	Rett syndrome	2022-04-28	reviewed by expert panel	curation	The allele frequency of the p.Pro419Ser variant in MECP2 (NM_004992.3) is 0.02% in "Other" sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1) and additionally is present in three male individuals in gnomAD. The p.Pro419Ser variant is observed in at least 7 unaffected individuals (Baylor Genetic internal database, GeneDx internal database, PMID 16225173) (BS2). The p.Pro419Ser variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). The p.Pro419Ser variant has been observed in at least 2 individuals with neurodevelopmental disorders (PMID 32457807, 16225173) (PS4_supporting), however in these studies MECP2 was the only gene sequenced. In summary the p.Pro419Ser variant in MECP2 is classified as benign for Rett Syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5) and the PS4_supporting evidence is not considered inconsistent with the final benign classification.
GeneDx	RCV000456515	SCV000191000	likely benign	not provided	2020-02-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Previously reported as a variant of uncertain significance in a female diagnosed with Rett syndrome and her unaffected mother (Gauthier et al., 2005); This variant is associated with the following publications: (PMID: 16225173, 32457807)
Genetic Services Laboratory, University of Chicago	RCV000168707	SCV000247946	uncertain significance	not specified	2013-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088911	SCV000544612	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-12-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000766081	SCV000897556	uncertain significance	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
CeGaT Center for Human Genetics Tuebingen	RCV000456515	SCV001150511	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415628	SCV002679839	likely benign	Inborn genetic diseases	2018-06-20	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.
Centre for Population Genomics, CPG	RCV002260619	SCV004101599	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 variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1).
PreventionGenetics, part of Exact Sciences	RCV004532632	SCV004750841	benign	MECP2-related disorder	2024-06-15	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).