Submissions for variant NM_001110792.2(MECP2):c.455C>T (p.Ala152Val)

dbSNP: rs28934908

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000224266	SCV000202987	pathogenic	not provided	2014-04-10	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224266	SCV000281580	pathogenic	not provided	2014-08-26	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414791	SCV000492695	likely pathogenic	Motor delay; Micrognathia; Hearing impairment; Downslanted palpebral fissures; Microcephaly; Stenosis of the external auditory canal; Intellectual disability; Postnatal growth retardation	2015-09-10	criteria provided, single submitter	clinical testing
TIDEX, University of British Columbia	RCV000020628	SCV000586832	pathogenic	Rett syndrome		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544176	SCV000645665	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 140 of the MECP2 protein (p.Ala140Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurodevelopmental disorders (PMID: 11007980, 12325019, 25473036, 26350204, 27465203). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11823). 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. Experimental studies have shown that this missense change does not substantially affect MECP2 function (PMID: 12843318, 21831886, 26418480). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000012596	SCV000782728	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2017-09-22	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197458	SCV001368203	likely pathogenic	Autism, susceptibility to, X-linked 3	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249626	SCV001423701	pathogenic	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	2018-07-03	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS3, PM1, PM2, PS4_Moderate, PP1, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257756	SCV001434568	likely pathogenic	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000224266	SCV001447675	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001374894	SCV001572181	pathogenic	Neurodevelopmental disorder	2020-04-03	criteria provided, single submitter	clinical testing
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV000224266	SCV001760753	likely pathogenic	not provided	2018-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000224266	SCV001823566	pathogenic	not provided	2020-07-17	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30542205, 33144682, 32581362, 32371413, 12325019, 27465203, 24328834, 25473036, 29431277, 30536762, 31273722, 11885030, 11007980, 26418480, 26350204, 11805248, 27929079, 12843318, 21831886)
CeGaT Center for Human Genetics Tuebingen	RCV000224266	SCV002063369	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326676	SCV002629906	pathogenic	Inborn genetic diseases	2022-09-29	criteria provided, single submitter	clinical testing	The c.419C>T (p.A140V) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to T substitution at nucleotide position 419, causing the alanine (A) at amino acid position 140 to be replaced by a valine (V)._x000D_ _x000D_ Based on the available evidence, the MECP2 c.419C>T (p.A140V) alteration is classified as pathogenic for X-linked recessive MECP2-related neurodevelopmental disorder; however, this variant is unlikely to be causative of X-linked dominant typical RTT, atypical RTT, or neonatal severe encephalopathy. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in numerous individuals and families with affected males demonstrating moderate to severe intellectual disability and movement disorders, and carrier females showing mild intellectual disability or who appear to be unaffected (Orrico, 2000; Couvert, 2001; Lambert, 2016). In addition, co-segregation with clinical findings has been described across multiple families (Orrico, 2000; Winnepenninckx, 2002; Lambert, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002466399	SCV002761554	pathogenic	Syndromic X-linked intellectual disability Lubs type	2022-05-23	criteria provided, single submitter	clinical testing	The MECP2 c.455C>T variant is classified as PATHOGENIC (PS4, PP1_strong, PM2, PP3) The MECP2 c.455C>T variant is a single nucleotide change in exon 3/3 of the MECP2 gene, which is predicted to change the amino acid alanine at position 152 in the protein to valine. This recurrent variant has been reported in multiple individuals with a clinical presentation of X-linked syndromic Intellectual disability or non-classic Rett phenotype (PS4). This variant has been reported in dbSNP (rs28934908) but is absent from population databases (PM2). This variant has been reported to co-segregate with disease in a large number of individuals in multiple families (PMID:11007980, PMID:26350204, PMID:25473036, PMID:27465203, PMID:12325019) (PP1_strong). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has been reported in ClinVar as Pathogenic / Likely Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 11823) and is classified as damaging in the HGMD disease database (CM003325).
Lifecell International Pvt. Ltd	RCV000020628	SCV003923342	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing	A Hemizygote Missense variant c.419C>T in Exon 4 of the MECP2 gene that results in the amino acid substitution p.Ala140Val was identified. The observed variant has a minor allele frequency of 0.0 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variation ID: 11823). The variant has been previously reported by Winnepenninckx B, et al., 2002. Experimental study by Agarwal N, et al., 2011 showed MECP2 mutants affected in heterochromatin accumulation further exhibited the shortest residence time on heterochromatin, and their dysfunction lead to Rett syndrome. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Eurofins-Biomnis	RCV000012596	SCV003935107	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2022-11-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012596	SCV004027691	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2023-07-05	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5_STR,PS2_MOD,PM2_SUP,PP2,PP3
Centre for Population Genomics, CPG	RCV000012596	SCV004808968	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2024-03-08	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: Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 11309367, 30536762, 11007980, 11885030, ClinVar Variation ID: 11823) Co-segregation with disease in multiple affected family members (3-4 informative meiosis) informative meiosis (PP1_Moderate). (PMID: 11007980, 11885030) Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012596	SCV005399578	pathogenic	X-linked intellectual disability-psychosis-macroorchidism 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 display X-linked recessive inheritance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes, 0 hemizygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated methyl-CpG binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in multiple individuals with non-classic Rett syndrome or moderate-severe intellectual disability with movement disorder (ClinVar, GeneReviews, DECIPHER). (SP) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001249626	SCV005418117	pathogenic	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		criteria provided, single submitter	clinical testing	PP1_Strong+PS4_Moderate+PM2_Supporting+PP3+PP4+PS3_Moderate
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV002466399	SCV005438628	pathogenic	Syndromic X-linked intellectual disability Lubs type	2024-12-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Heidelberg University	RCV004819207	SCV005440672	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome	2024-07-12	criteria provided, single submitter	clinical testing
OMIM	RCV000012596	SCV000032831	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2002-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000020628	SCV000041141	not provided	Rett syndrome		no assertion provided	literature only
RettBASE	RCV000020628	SCV000188092	likely pathogenic	Rett syndrome	2016-04-26	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001004016	SCV001162077	likely pathogenic	Atypical behavior		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224266	SCV001742501	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224266	SCV001808146	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224266	SCV001969847	pathogenic	not provided		no assertion criteria provided	clinical testing
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000224266	SCV004175157	pathogenic	not provided	2023-04-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734513	SCV005360864	pathogenic	MECP2-related disorder	2024-06-15	no assertion criteria provided	clinical testing	The MECP2 c.419C>T variant is predicted to result in the amino acid substitution p.Ala140Val. This variant has been reported in several patients to be causative for X-linked intellectual disability with variable neurobehavioral and dysmorphic features (see for example, Orrico et al. 2000. PubMed ID: 11007980; Sheik et al. 2016. PubMed ID: 27929079; Lambert et al. 2016. PubMed ID: 27465203; Venkateswaran et al. 2014. PubMed ID: 24328834). In vitro functional studies demonstrate this variant affects MECP2 function (Nan et al. 2007. PubMed ID: 17296936; Sheikh et al. 2016. PubMed ID: 27929079) and a mouse model demonstrates this variant disrupts neuronal signaling. This variant has not been reported in a large population database, indicating this variant is rare. Taken together, this variant is interpreted as pathogenic.