Submissions for variant NM_001110792.2(MECP2):c.961C>T (p.Arg321Trp)

dbSNP: rs61751444

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000170241	SCV002569941	pathogenic	Rett syndrome	2022-07-28	reviewed by expert panel	curation	The c.925C>T p.(Arg309Trp) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Arg309Trp) variant has been observed in at least 5 individuals, including males, with variable neurodevelopmental phenotypes consistent with MECP2-related disease (PMID 26936630, 29655203, 29720203, 28837158, 31178897, 30536762, 32214227) (PS4, PP4). One of the reported individuals with this variant was also found to be heterozygous for a de novo (biological parentage confirmed) SMC3 frameshift variant (PMID 31178897). The p.(Arg309Trp) variant has been reported as a de novo occurrence (biological parentage both confirmed and unconfirmed) in at least 3 of these individuals (PMID 31178897, 26936630) (PS2_very strong). Additional family studies have found the p.(Arg309Trp) variant to be maternally inherited in at least 2 cases (PMID 29720203, 26936630), and inherited from an unaffected mosaic parent in at least 1 case (PMID 28837158). Computational prediction analysis tools are inconclusive for this variant. In summary, the c.925C>T p.(Arg309Trp) variant in MECP2 is classified as Pathogenic for MECP2-related disease based on the ACMG/AMP criteria (PS2_very strong, PS4, PM2_supporting, PP4).
GeneDx	RCV000133293	SCV000190988	pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28027854, 20479760, 21160487, 17084570, 23810759, 26936630, 28089766, 30536762, 29655203, 29720203, 28837158, 31178897, 32214227)
Genetic Services Laboratory, University of Chicago	RCV000170241	SCV000248007	pathogenic	Rett syndrome	2017-06-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000133293	SCV000343620	likely pathogenic	not provided	2016-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000133293	SCV000575669	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624661	SCV000741171	likely pathogenic	Inborn genetic diseases	2015-12-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169947	SCV000807252	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found four times in our laboratory (in 3 males and 1 female): maternally inherited in a 6-year-old male with global delays, stereotypic hand movements, hypotonia, failure to thrive; de novo in a 3-year-old female with global delays and hypotonia; maternally inherited in a 4-year-old male with gloabal delays, dysmorphisms, short stature, macrocehaly, retractile testis, hypothyroidism; de novo in a 2-year-old male with global delay, hypotonia, epilepsy, relative macrocephaly
Mayo Clinic Laboratories, Mayo Clinic	RCV000170241	SCV000809080	likely pathogenic	Rett syndrome	2018-04-12	criteria provided, single submitter	clinical testing
Biochemistry Laboratory of CDMU, Chengde Medical University	RCV000170241	SCV000899194	likely pathogenic	Rett syndrome		criteria provided, single submitter	case-control
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000851523	SCV000994583	pathogenic	Intellectual disability	2019-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV001049007	SCV001213039	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 309 of the MECP2 protein (p.Arg309Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability and/or clinical characteristics of Rett syndrome (PMID: 17084570, 20479760, 21160487, 23810759, 26936630, 29720203, 30536762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143749). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000170241	SCV001251808	pathogenic	Rett syndrome	2020-05-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000133293	SCV001446400	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV000133293	SCV001760747	likely pathogenic	not provided	2019-10-28	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000169947	SCV001837627	likely pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome		criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000170241	SCV003836688	pathogenic	Rett syndrome	2020-06-02	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000170241	SCV003932164	pathogenic	Rett syndrome	2023-03-02	criteria provided, single submitter	clinical testing	PS2_Very Strong, PS4, PM2, PP3
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000170241	SCV004045783	pathogenic	Rett syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003984819	SCV004801240	pathogenic	Syndromic X-linked intellectual disability Lubs type	2024-03-14	criteria provided, single submitter	research
RettBASE	RCV000169947	SCV000188302	uncertain significance	X-linked intellectual disability-psychosis-macroorchidism syndrome	2013-12-05	no assertion criteria provided	curation
RettBASE	RCV000170240	SCV000222571	uncertain significance	Autism, susceptibility to, X-linked 3	2013-12-05	no assertion criteria provided	curation
RettBASE	RCV000170241	SCV000222572	uncertain significance	Rett syndrome	2013-12-05	no assertion criteria provided	curation
GeneReviews	RCV000170241	SCV000998928	not provided	Rett syndrome		no assertion provided	literature only
Section for Clinical Neurogenetics, University of Tübingen	RCV000170241	SCV001156091	pathogenic	Rett syndrome	2019-08-01	no assertion criteria provided	research