Submissions for variant NM_001110792.2(MECP2):c.535C>T (p.Arg179Trp)

dbSNP: rs61748420

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000193537	SCV003853559	pathogenic	Rett syndrome	2021-12-13	reviewed by expert panel	curation	The p.Arg167Trp variant (NM_004992.3) in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with MECP2-related disorders through testing completed at GeneDx (PS2_very strong). The variant has been reported to segregate in at least five informative meioses in published literature (Couvert et al., 2001) (PP1_strong). The p.Arg167Trp variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg167Trp variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PP1_strong, PM2_supporting).
Genetic Services Laboratory, University of Chicago	RCV000193537	SCV000247973	pathogenic	Rett syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000498300	SCV000589567	pathogenic	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Heterozygous carrier females with resting tremors have been reported (PMID: 14598336); Functional studies show the R167W mutant protein is defective, as when expressed in mouse myoblast cells, chromocenter clustering reduced in size and increased in number (PMID: 27929079); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30083362, 26490184, 11309367, 26350204, 27323888, 27929079, 30536762, 35032046, 34271245, 31440721, 14598336)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688107	SCV000815707	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-12-09	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 167 of the MECP2 protein (p.Arg167Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MECP2-related conditions (PMID: 11309367, 14598336, 26350204, 26490184, 27929079, 30083362). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143603). 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: 27929079). For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000193537	SCV001164193	uncertain significance	Rett syndrome	2017-11-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000498300	SCV001246090	pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000498300	SCV001447614	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252000	SCV002523239	pathogenic	See cases	2019-09-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM2, PP3
Ambry Genetics	RCV002336285	SCV002640663	pathogenic	Inborn genetic diseases	2019-04-26	criteria provided, single submitter	clinical testing	The p.R167W pathogenic mutation (also known as c.499C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 499. The arginine at codon 167 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation segregated with disease in four affected males over two generations within a large family and was absent in a healthy maternally related male (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6). Affected males in this family were noted to have moderate intellectual disability, microcephaly, seizures, hypoactivity, poor coordination, brisk tendon reflexes, difficulties with written language, verbal stereotypies, and resting tremors, which were also observed in two obligate carrier females (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6; Gomot M et al. Am. J. Med. Genet. A, 2003 Dec;123A:129-39). In another family, this mutation was detected in 3 affected brothers and their mother, who demonstrated skewed X-inactivation (Bianciardi L et al. J. Hum. Genet., 2016 Feb;61:95-101). C2C12 cells expressing this mutation demonstrated an increased number of chromocenters with decreased size (Sheikh TI et al. Sci Rep, 2016 12;6:38590). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics	RCV000498300	SCV002770825	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	This variant has been reported in multiple male individuals with an X-linked intellectual developmental disorder. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function shows this variant causes a chromatin binding defect, increasing the number of chromocenters and decreasing their size (PMID: 27929079). Further research is needed to determine disease consequence. This variant segregates with disease in multiple families.
Eurofins-Biomnis	RCV000133142	SCV003935091	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2022-11-23	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV000193537	SCV004808992	pathogenic	Rett syndrome	2024-03-13	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 3.0, this variant is classified as pathogenic. At least the following criteria are met: Co-segregation with disease in multiple affected family members (> 5 informative meiosis) (PP1_Strong). PMID: 11309367 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).(PMID: 11309367, 30536762, ClinVar Variation ID: 143603) This variant is absent from gnomAD (PM2_Supporting).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000193537	SCV005400181	pathogenic	Rett syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with MECP2-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability demonstrate X-linked recessive inheritance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and typically affects hemizygous males where the variant was inherited from an asymptomatic mother (PMID: 26490184, ClinVar). However, rare reports of affected females have been described, who presented with nonprogressive resting tremour, epilepsy or a neuropsychiatric phenotype [DECIPHER, PMID: 11309367, Gonzaga-Jauregui C, et al. (2021)]. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Daryl Scott Lab, Baylor College of Medicine	RCV005222767	SCV005871116	pathogenic	MECP2-related disorder	2024-01-01	criteria provided, single submitter	clinical testing	PS2_very strong, PP1_strong, PM2_supporting
RettBASE	RCV000133142	SCV000188134	uncertain significance	X-linked intellectual disability-psychosis-macroorchidism syndrome	2011-02-15	no assertion criteria provided	curation
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000498300	SCV001931110	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000498300	SCV001972154	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000498300	SCV002037458	likely pathogenic	not provided		no assertion criteria provided	clinical testing