ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.961C>T (p.Arg321Trp) (rs61751444)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000133293 SCV000190988 pathogenic not provided 2018-01-03 criteria provided, single submitter clinical testing The R309W variant in the MECP2 gene has been reported previously in multiple individuals with variable clinical features including intellectual disability, autism spectrum disorder, seizures, and Rett syndrome (Campos et al., 2007; Hadzsiev et al., 2011; Piton et al., 2011; Maortua et al., 2013; Schonewolf-Greulich et al., 2016; Ronen et al., 2017). This variant has also been observed in the hemizygous state in patients previously tested at GeneDx with features of a MECP2-related disorder. It is not observed in large population cohorts (Lek et al., 2016). The R309W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a conserved position in the transcriptional repression domain (TRD) where many pathogenic missense variants have been reported in association with MECP2-related disorders (Stenson et al., 2014). We interpret R309W as a pathogenic variant.
Genetic Services Laboratory,University of Chicago RCV000170241 SCV000248007 pathogenic Rett syndrome 2017-06-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000133293 SCV000343620 likely pathogenic not provided 2016-10-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik 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 Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Baylor Genetics RCV000169947 SCV000807252 pathogenic Mental retardation, X-linked, syndromic 13 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 Genetic Testing 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 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 309 of the MECP2 protein (p.Arg309Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with intellectual disability and/or clinical characteristics of Rett syndrome (PMID: 17084570, 23810759, 21160487, 29720203, 26936630, 30536762), including several de novo observations (PMID: 20479760, 26936630). ClinVar contains an entry for this variant (Variation ID: 143749). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
RettBASE RCV000169947 SCV000188302 uncertain significance Mental retardation, X-linked, syndromic 13 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 pathogenic Rett syndrome 2019-09-16 no assertion criteria provided literature only
Section for Clinical Neurogenetics,University of Tübingen RCV000170241 SCV001156091 pathogenic Rett syndrome 2019-08-01 no assertion criteria provided research

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