Submissions for variant NM_001110792.2(MECP2):c.784C>T (p.Arg262Cys)

dbSNP: rs141382970

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	RCV003448285	SCV004175917	likely benign	Rett syndrome	2023-12-06	reviewed by expert panel	curation	The c.748C>T p.Arg250Cys variant in MECP2 (NM_004992.3) is present in 1 XY and 4 XX individuals in gnomAD (0.0034% in the European non-Finnish population) (not sufficient to meet BS1 criteria). The p.Arg250Cys variant is observed in at least 2 unaffected individuals (GeneDx internal data) (BS2). The p.Arg250Cys variant has been observed in at least 1 individual with RTT-like disease (PMID 30405208); however PS4 cannot be applied at any strength due to the gnomAD frequency. Computational prediction analysis tools are inconclusive for this variant (criteria not met). Alternative missense variants (p.Arg250Gly and p.Arg250His) have previously been identified within this codon, however they are not considered to be pathogenic variants (PMID 30405208; RettBASE: RettSyndrome.org Variation Database mecp2.chw.edu.au). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the c.748C>T p.Arg250Cys variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2).
Genetic Services Laboratory, University of Chicago	RCV000192395	SCV000247992	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757451	SCV000885676	uncertain significance	not provided	2018-03-09	criteria provided, single submitter	clinical testing	The MECP2 c.748C>T; p.Arg250Cys variant (rs141382970), to our knowledge, has not been reported in the medical literature but is reported as benign by one laboratory in ClinVar (Variation ID: 211466). This variant is observed in the general population at an overall frequency of 0.002% (5/178458 alleles, including 1 hemizygote) in the Genome Aggregation Database. The arginine at codon 250 is highly conserved, and computational algorithms (PolyPhen2, SIFT) predict this variant to be deleterious. However, additional variants at this codon (p.Arg250Arg, p.Arg250His) are considered as polymorphisms that do not cause disease (see link for Rett database). Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Link to Rett database: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic
Invitae	RCV001043679	SCV001207437	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2022-05-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 250 of the MECP2 protein (p.Arg250Cys). This variant is present in population databases (rs141382970, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 30405208). ClinVar contains an entry for this variant (Variation ID: 211466). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000757451	SCV001747677	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000757451	SCV002504140	likely benign	not provided	2019-04-19	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
PreventionGenetics, part of Exact Sciences	RCV003390928	SCV004120475	uncertain significance	MECP2-related condition	2024-01-22	criteria provided, single submitter	clinical testing	The MECP2 c.748C>T variant is predicted to result in the amino acid substitution p.Arg250Cys. This variant has been reported in a patient with a MECP2 related disorder; however, no additional studies confirmed its pathogenicity (Zhang et al. 2019. PubMed ID: 30405208). This variant is reported in 0.0063% of alleles in individuals of European (Finnish) descent in gnomAD. It has been detected in the heterozygous and hemizygous states in both the gnomAD database and the PreventionGenetics internal database at a frequency that is higher than expected for a disease-causing MECP2 variant, and is observed in individuals not expected to have a MECP2-related disease. Alternate missense changes at the same amino acid position have been reported in gnomAD, and as non-disease-causing variants in the Rett database (http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic; https://gnomad.broadinstitute.org/region/X-153296511-153296551). This variant has conflicting classifications in ClinVar of Uncertain, Likely Benign, and Benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/211466/). Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.