ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1000C>G (p.Pro334Ala)

dbSNP: rs61751449
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV002262751 SCV002546213 pathogenic not provided 2022-05-01 criteria provided, single submitter clinical testing MECP2: PS2, PM2, PM5, PS4:Moderate
Centre for Population Genomics, CPG RCV000169949 SCV004232199 likely pathogenic Rett syndrome 2024-01-09 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 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in at least one individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID: 11462237, PMID: 16225173 Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). PMID: 16473305, PMID: 11462237, PMID: 18174559, ClinVar database(Variation ID: 143753)
Invitae RCV003522939 SCV004299163 pathogenic Severe neonatal-onset encephalopathy with microcephaly 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 322 of the MECP2 protein (p.Pro322Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Rett syndrome (PMID: 10814719, 11462237, 15737703, 16225173). This variant is also known as 1038C>G. ClinVar contains an entry for this variant (Variation ID: 143753). 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 not expected to disrupt MECP2 protein function with a negative predictive value of 95%. This variant disrupts the p.Pro322 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15526954, 17089071, 29718204). 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.
RettBASE RCV000169949 SCV000188307 uncertain significance Rett syndrome 2012-05-18 no assertion criteria provided curation

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