ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1477G>A (p.Val493Met) (rs193922678)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000724867 SCV000191003 uncertain significance not provided 2016-06-17 criteria provided, single submitter clinical testing The V481M missense change was previously identified in a female with a history of developmental regression and fulfilled the criteria for Rett syndrome (Zvereff et al., 2012). Family history was unknown and the authors reported the substitution as a variant of unknown significance because in-silico algorithms were not consistent in their predictions of whether V481M was pathogenic. NHLBI Exome Variant Project has not identified V481M in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is conservative as both Valine and Methionine are uncharged, non-polar amino acid residues. V481M alters a highly conserved position in the MECP2 protein. While several in-silico algorithms predict it may be damaging to the structure/function of the protein, one model predicts it may be benign. In addition, other missense variants at nearby codons (T479M, P480S) are classified as benign variants. Therefore, based on the currently available information, it is unclear whether V481M is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Genetic Services Laboratory,University of Chicago RCV000194612 SCV000247954 uncertain significance not specified 2013-02-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724867 SCV000332088 uncertain significance not provided 2015-06-15 criteria provided, single submitter clinical testing
Invitae RCV001057144 SCV001221621 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2019-02-15 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 481 of the MECP2 protein (p.Val481Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Rett syndrome (PMID: 22277191). ClinVar contains an entry for this variant (Variation ID: 36492). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000030164 SCV000052822 uncertain significance Rett syndrome 2015-03-13 no assertion criteria provided clinical testing The Val493Met variant has not been identified in 87757 chromosomes by the Exome Aggregation Consortium (ExAC, The Valine at position 493 is highly conserved in evolution, though computational tools do not provide strong support for or against an impact to the protein. The variant has been reported previously in two female patients with Rett syndrome (Fong et al 2009/MECP2 database and Zvereff et al 2012), however family history was not provided. This variant is more likely pathogenic but additional studies are needed to fully assess its clinical significance.
RettBASE RCV000030164 SCV000187995 uncertain significance Rett syndrome 2012-09-27 no assertion criteria provided curation

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