ClinVar Miner

Submissions for variant NM_004992.3(MECP2):c.378-3C>G (rs267608465)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000144115 SCV000329582 likely pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the MECP2 gene. The c.378-3 C>G splice site variant in the MECP2 gene has been previously reported as a pathogenic variant in individuals with classic Rett syndrome (Fukuda et al., 2005; Condie et al., 2010; Kalman et al., 2014; RettBASE). In two of the affected individuals the variant was apparently de novo (Fukuda et al., 2005; Condie et al., 2010). The c.378-3 C>G variant is not observed in large population cohorts (Lek et al., 2016). In silico analysis predicts that the c.378-3 C>G variant may destroy or reduce the quality of the natural splice acceptor site in intron 3 and create a cryptic splice acceptor site, leading to abnormal splicing. However, in the absence of RNA/functional studies the actual effect of this variant is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Integrated Genetics/Laboratory Corporation of America RCV000170202 SCV000917616 likely pathogenic Rett syndrome 2018-10-11 criteria provided, single submitter clinical testing Variant summary: MECP2 c.378-3C>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site. Five predict the variant creates a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 176790 control chromosomes (gnomAD). The variant, c.378-3C>G, has been reported in the literature in one female with classical RTT (Fukuda_2005), and in one male in which the mutation was presumed de novo (absent in the mother but maternity not explicitly confirmed) who had aquired microcephaly, regression of milestones, mitochondrial dysfunction, and episodic rigidity (Condie_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000170202 SCV000928393 likely pathogenic Rett syndrome 2018-11-30 criteria provided, single submitter clinical testing PS2, PM2, PP4, PP5
Invitae RCV000800164 SCV000939864 likely pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-05-24 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the MECP2 gene. It does not directly change the encoded amino acid sequence of the MECP2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in a male affected with microcephaly, hypotonia, and absent reflexes (PMID: 20142466), in an individual affected with clinical features of Rett syndrome (PMID: 15737703), and in another male affected with motor regression, speech impairment, gait abnormality, transient hand stereotypies, and microcephaly (PMID: 30536762). This variant is also known as Ex4 acceptor site in the literature. ClinVar contains an entry for this variant (Variation ID: 156068). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000857 SCV001157932 pathogenic not specified 2018-10-03 criteria provided, single submitter clinical testing The MECP2 c.378-3C>G variant (rs267608465), is reported in the literature in multiple females affected with classic Rett syndrome (Fukuda 2005, Kalman 2014), and also in a male affected with Rett syndrome (Condie 2010). This variant is reported as pathogenic in ClinVar (Variation ID: 156068), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 3, which is likely to disrupt gene function by creating a novel spice acceptor site that is predicted to cause a frameshift. Based on available information, the c.378-3C>G variant is considered to be pathogenic. References: Condie J et al. Acquired microcephaly, regression of milestones, mitochondrial dysfunction, and episodic rigidity in a 46,XY male with a de novo MECP2 gene mutation. J Child Neurol. 2010 May;25(5):633-6. Fukuda T et al. Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. Brain Dev. 2005 Apr;27(3):211-7. Kalman LV et al. Development of a genomic DNA reference material panel for Rett syndrome (MECP2-related disorders) genetic testing. J Mol Diagn. 2014 Mar;16(2):273-9.
RettBASE RCV000144115 SCV000189191 not provided not provided no assertion provided not provided
RettBASE RCV000170202 SCV000222531 pathogenic Rett syndrome 2008-02-18 no assertion criteria provided curation

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