ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.950A>G (p.Lys317Arg)

dbSNP: rs61751441
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002515934 SCV003445865 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2022-05-12 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 305 of the MECP2 protein (p.Lys305Arg). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MECP2 function (PMID: 23770565). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. ClinVar contains an entry for this variant (Variation ID: 143745). This missense change has been observed in individual(s) with Rett syndrome (PMID: 11402105, 15737703). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
Centre for Population Genomics, CPG RCV000133289 SCV004098827 likely pathogenic Rett syndrome 2023-08-14 criteria provided, single submitter curation This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria.Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as Likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3_supporting, PMID: 23770565). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease (PS4_Moderate, Rettbase internal database, PMID: 11055898, PMID: 11738885, PMID: 15737703). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).
RettBASE RCV000133289 SCV000188297 uncertain significance Rett syndrome 2008-02-18 no assertion criteria provided curation

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