ClinVar Miner

Submissions for variant NM_004992.3(MECP2):c.1162C>T (p.Pro388Ser) (rs61753000)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726321 SCV000343777 uncertain significance not provided 2016-08-17 criteria provided, single submitter clinical testing
GeneDx RCV000726321 SCV000190996 uncertain significance not provided 2014-05-07 criteria provided, single submitter clinical testing The P388S missense change has been previously reported as a de novo variant in a female with severe congenital psychomotor delay, infantile spasms beginning at 5 months, and sudden renal failure at age 5 (Conforti el al., 2003). Of note, Conforti reports this variant using different protein nomenclature (p.S388P) but the same c.1162 C>T. P388S was subsequently identified in a female with a clinical diagnosis of Rett syndrome; however parental studies were not performed (Zahorakova et al., 2007). A different amino acid substitution at the same position (P388L) was reported as a disease-causing mutation in a female with Rett syndrome; however, the change was inherited from her unaffected mother (Milunsky et al., 2001). P388S was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, but is not conserved in more distantly related species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
RettBASE RCV000169943 SCV000187900 uncertain significance Rett syndrome 2007-11-15 no assertion criteria provided curation
SIB Swiss Institute of Bioinformatics RCV000169943 SCV000803542 uncertain significance Rett syndrome 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Rett syndrome, in X-linked Dominant manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:12567420).

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