ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.604C>T (p.Arg202Cys) (rs587783137)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000144810 SCV000191042 pathogenic not provided 2015-06-12 criteria provided, single submitter clinical testing The Arg190Cys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as a positively charged Arginine residue is replaced by an uncharged Cysteine residue and the gain of a Cysteine may affect disulfide bond formation in the MECP2 protein. Arg190Cys alters a highly conserved and exposed position in a DNA binding motif of the protein and multiple in-silico algorithms predict it to be damaging to the structure/function of the protein. However, other missense variants at nearby codons have been classified as benign. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s).
Invitae RCV000645120 SCV000766862 uncertain significance Severe neonatal-onset encephalopathy with microcephaly 2017-09-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 190 of the MECP2 protein (p.Arg190Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587783137, ExAC 0.002%), including at least one homozygous individual. This variant has been reported in an individual affected with schizophrenia (PMID:24776741). ClinVar contains an entry for this variant (Variation ID: 156667). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Baylor Genetics RCV000680040 SCV000807479 uncertain significance Rett syndrome 2017-09-01 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory in a 7-year-old female with global delays, regression, autism, hypotonia, epilepsy, aggressive behavior. Mom did not carry the variant, father not tested

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