Submissions for variant NM_001110792.2(MECP2):c.1244C>T (p.Pro415Leu)

gnomAD frequency: 0.00004  dbSNP: rs587783107

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	RCV003235062	SCV003934951	likely benign	Rett syndrome	2023-05-22	reviewed by expert panel	curation	The p.Pro403Leu variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (internal database - GeneDx; internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions. The p.Pro403Leu variant in MECP2 is present in 3 female individuals in gnomAD (0.0015%) (not sufficient to meet BS1 criteria). In summary, the p.Pro403Leu variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2).
GeneDx	RCV000144776	SCV000190997	likely benign	not provided	2020-03-31	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant does not alter protein structure/function Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001340957	SCV001534792	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2023-12-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345451	SCV002649636	uncertain significance	Inborn genetic diseases	2017-11-17	criteria provided, single submitter	clinical testing	The p.P403L variant (also known as c.1208C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 1208. The proline at codon 403 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004532631	SCV004725790	likely benign	MECP2-related disorder	2023-01-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).