ClinVar Miner

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

dbSNP: rs28934908
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Total submissions: 27
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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
Invitae 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).
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

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