ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.459C>G (p.Tyr153Ter) (rs61748396)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623504 SCV000742651 pathogenic Inborn genetic diseases 2017-06-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000729616 SCV000857290 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000729616 SCV000885677 pathogenic not provided 2017-10-04 criteria provided, single submitter clinical testing The MECP2 c.423C>G; p.Tyr141Ter variant (rs61748396) has been reported in several individuals with Rett syndrome (see Buyse 2000, De Bona 2000, Giunti 2001, Nielsen 2001, Vacca 2001, Yamada 2001, Zahorakova 2007). It is reported as pathogenic in ClinVar (Variation ID:11833), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database, 1000 Genomes Project). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Buyse IM et al. Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. Am J Hum Genet. 2000 Dec;67(6):1428-36. De Bona C et al. Preserved speech variant is allelic of classic Rett syndrome. Eur J Hum Genet. 2000 May;8(5):325-30. Giunti L et al. Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation. Brain Dev. 2001 Dec;23 Suppl 1:S242-5. Nielsen JB et al. MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern. Eur J Hum Genet. 2001 Mar;9(3):178-84. Vacca M et al. Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females. J Mol Med (Berl). 2001;78(11):648-55. Yamada Y et al. Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation. Hum Mutat. 2001 Sep;18(3):253. Zahorakova D et al. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007;52(4):342-8. Epub 2007 Feb 15.
Integrated Genetics/Laboratory Corporation of America RCV000170108 SCV000917617 pathogenic Rett syndrome 2017-10-04 criteria provided, single submitter clinical testing Variant summary: The MECP2 c.423C>G (p.Tyr141X) variant results in a premature termination codon, predicted to cause a truncated or absent MECP2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.502C>T, p.Arg168X; c.710delG, p.Gly237fsX11; c.730C>T, p.Gln244X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 177332 control chromosomes (gnomAD and Zahorakova_2007) and has been reported in numerous RTT patients in the literature from a broad range of ethnicities (Bienvenu_2002, Fukuda_2005, Li_2007, Nielsen_2001, Zahorakova_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV001049210 SCV001213250 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-12-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MECP2 gene (p.Tyr141*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 346 amino acids of the MECP2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Rett syndrome (PMID: 10854091). ClinVar contains an entry for this variant (Variation ID: 11833). This variant disrupts the C-terminus of the MECP2 protein. Other variant(s) that disrupt this region (p.Pro389*) have been determined to be pathogenic (PMID: 17387578, 19914908). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012606 SCV000032841 pathogenic Atypical Rett syndrome 2001-04-01 no assertion criteria provided literature only
RettBASE RCV000133106 SCV000188096 pathogenic Angelman syndrome 2008-02-18 no assertion criteria provided curation
RettBASE RCV000170108 SCV000222430 pathogenic Rett syndrome 2008-02-18 no assertion criteria provided curation

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