Submissions for variant NM_001110792.2(MECP2):c.727G>A (p.Gly243Arg)

gnomAD frequency: 0.00002  dbSNP: rs587783139

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV002472364	SCV002769734	likely benign	Rett syndrome	2022-12-08	reviewed by expert panel	curation	The p.Gly231Arg variant in MECP2 (NM_004992.3) is observed in 3 unaffected individuals (PMID: 28250423, internal database) (BS2). The p.Gly243Arg variant is reported in one male with autism, and one female with intellectual and developmental disabilities and seizures (PMID: 28250423, 24321989) (PS4 not met). The p.Gly231Arg variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Gly231Arg variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5).
GeneDx	RCV000726052	SCV000191044	uncertain significance	not provided	2016-04-14	criteria provided, single submitter	clinical testing	The G231R variant was identified previously in a female with seizures and intellectual and developmental disabilities; however, no additional information was provided to unequivocally demonstrate that it is pathogenic and parental studies were not performed (Sundaram et al., 2014). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G231R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and missense variants in a nearby residue (P225R, P225T) have been reported in RettBASE and the Human Gene Mutation Database in association with Rett syndrome (MECP2 Variation Database; Stenson et al., 2014). However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000726052	SCV000341519	uncertain significance	not provided	2016-05-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000718449	SCV000849312	likely benign	History of neurodevelopmental disorder	2017-03-17	criteria provided, single submitter	clinical testing	In silico models in agreement (benign) ;Other data supporting benign classification
New York Genome Center	RCV002265623	SCV002548912	uncertain significance	X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome	2021-07-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514781	SCV003474300	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-07-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532634	SCV004708675	likely benign	MECP2-related disorder	2023-11-17	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).