Submissions for variant NM_001110792.2(MECP2):c.1018C>G (p.Leu340Val)

gnomAD frequency: 0.00001  dbSNP: rs267608556

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000133302	SCV005419053	likely benign	Rett syndrome	2024-10-30	reviewed by expert panel	curation	The p.Leu328Val variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). The p.Leu328Val variant is found in at least 2 patients with an alternate molecular basis of disease (internal database - Invitae; internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Leu328Val variant in MECP2 in gnomAD v4.1 is 0.00004283 in European (Finnish) population (not sufficient to meet BS1 criteria). In summary, the p.Leu328Val variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001372487	SCV001569155	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 328 of the MECP2 protein (p.Leu328Val). This variant is present in population databases (rs267608556, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 16473305). ClinVar contains an entry for this variant (Variation ID: 143756). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001753520	SCV001985475	uncertain significance	not provided	2020-04-16	criteria provided, single submitter	clinical testing	Previously reported in a female patient with a clinical diagnosis of Rett syndrome, however additional clinical details were not provided (Philippe et al., 2006); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16473305)
Centre for Population Genomics, CPG	RCV000133302	SCV004232218	uncertain significance	Rett syndrome	2024-01-15	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 a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Has been observed in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting).PMID: 16473305 , ClinVar Variation ID:143756
RettBASE	RCV000133302	SCV000188311	uncertain significance	Rett syndrome	2008-01-21	no assertion criteria provided	curation