ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.940C>T (p.Pro314Ser) (rs61751373)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001067586 SCV001232654 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2020-01-15 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 302 of the MECP2 protein (p.Pro302Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Rett syndrome (PMID: 17387578), and has also been observed to be de novo in an individual affected with clinical features of MECP2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 143735). 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. This variant disrupts the p.Pro302 amino acid residue in MECP2. Other variants that disrupt this residue have been observed in individuals with MECP2-related conditions (PMID: 10767337, 10814718, 10814719, 15737703), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286649 SCV001473257 likely pathogenic none provided 2020-01-30 criteria provided, single submitter clinical testing The MECP2 c.904C>T; p.Pro302Ser variant (rs61751373) is reported in the literature an individual with classical Rett syndrome (Zahorakova 2007). Additionally, other amino acid substitutions at this codon (p.Pro302Leu, p.Pro302Ala, p.Pro302Arg, p.Pro302His, p.Pro302Thr) have been reported in individuals with Rett syndrome (see link to RettBASE and references therein). The c.904C>T; p.Pro302Ser is reported in the ClinVar database (Variation ID: 143735) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 302 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this amino acid has been implicated in binding a co-repressor complex and one variant at this position, p.Pro302Arg, abolishes this interaction (Lyst 2013). Considering available information, this variant is classified as likely pathogenic. References: RettBASE: Zahorakova D et al. Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms. J Hum Genet. 2007;52(4):342-8.
RettBASE RCV000133278 SCV000188286 uncertain significance Rett syndrome 2007-11-01 no assertion criteria provided curation

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