ClinVar Miner

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

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Total submissions: 6
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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.
Invitae RCV000800164 SCV000939864 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2018-10-23 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 in an individual affected with clinical features of Rett syndrome (PMID: 15737703) and in a male affected with microcephaly, hypotonia, and absent reflexes (PMID: 20142466). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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
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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