ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1169C>T (p.Ala390Val) (rs201314910)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000132866 SCV000230271 benign not specified 2014-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000132866 SCV000728724 likely benign not specified 2017-11-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000694069 SCV000822496 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2018-06-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 378 of the MECP2 protein (p.Ala378Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs201314910, ExAC 0.02%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with MECP2-related disease. ClinVar contains an entry for this variant (Variation ID: 143341). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090499 SCV001246084 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000132866 SCV001362155 likely benign not specified 2019-05-31 criteria provided, single submitter clinical testing Variant summary: MECP2 c.1133C>T (p.Ala378Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 175188 control chromosomes (2 hemizygotes). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. c.1133C>T has been reported in the literature in one female individual affected with Rett Syndrome and patient's unaffected father (Fukuda_2005). This report suggests the variant does not associate with Rett Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
RettBASE RCV000132866 SCV000187846 benign not specified 2010-03-10 no assertion criteria provided curation

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