ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.490C>G (p.Pro164Ala) (rs179363900)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492792 SCV000582724 pathogenic not provided 2016-07-27 criteria provided, single submitter clinical testing The P152A variant was previously reported in a female with pervasive developmental disorder, obesity, and anabnormal EEG, with no obvious seizures (Adegbola et al., 2009). The variant was inherited from her father, who wasreported to have learning disabilities and obesity (Adegbola et al., 2009). Functional studies demonstrated thatP152A has an approximately 40% reduction in heterochromatin binding when over-expressed in cultured cells(Adegbola et al., 2009, Tai et al., 2016). The P152A variant and a missense variant in the same residue (P152R)have been reported multiple times in RettBase in association with Rett Syndrome. The P152A variant was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations The P152A variant is asemi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ insome properties. This substitution occurs at a position that is conserved across species. Therefore, the P152A isinterpreted to be a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763200 SCV000893819 pathogenic Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; Mental retardation, X-linked, syndromic 13; Rett syndrome; Autism, susceptibility to, X-linked 3 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000991003 SCV001142091 uncertain significance Rett syndrome 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001246099 SCV001419437 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2019-10-08 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 152 of the MECP2 protein (p.Pro152Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with MECP2-related conditions (PMID: 18989701, 27929079, 29655203). ClinVar contains an entry for this variant (Variation ID: 11844). This variant has been reported to affect the MECP2 protein function (PMID: 18989701, 27929079, 26842955). This variant disrupts the p.Pro152 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767337, 11241840, 11055898, 10814718, 23859859, 15173251 ). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012618 SCV000032853 pathogenic Rett syndrome, zappella variant 2009-01-01 no assertion criteria provided literature only
RettBASE RCV000133115 SCV000188106 pathogenic Mental retardation, X-linked, syndromic 13 2009-03-04 no assertion criteria provided curation

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