Submissions for variant NM_001110792.2(MECP2):c.915C>G (p.Ile305Met)

gnomAD frequency: 0.00004  dbSNP: rs587783140

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001800462	SCV002047344	benign	Rett syndrome	2021-12-13	reviewed by expert panel	curation	The p.Ile293Met variant (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Ile305Met variant is found in a patient with an alternate molecular basis of disease (GeneDx internal database) (BP5). The allele frequency of the p.Ile293Met variant in MECP2 is 0.00027% in the East Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). In summary, the p.Ile293Met variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5, BS1).
GeneDx	RCV000144814	SCV000191048	likely benign	not provided	2019-04-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32393352)
Beijing Children’s hospital, National Center for Children’s Health	RCV001090171	SCV001244199	likely pathogenic	Microcephaly; Intellectual disability; Psychomotor retardation; Severe underweight in infancy childhood and adolescence	2020-04-17	criteria provided, single submitter	research	The de novo mutation (DNM) c.879C>G (p.Ile293Met) is located in transcriptional repression domain (TBD) of MECP2 gene. Within the TBD region of 104 amino acids (from residue 219 to 322), 62 different pathogenic mutations have been identified (HGMD). In contrast, only one missense mutation (p.Thr240Ser) is probably a benign allele with a high-count (183 in In gnomAD). The Ile293Met variant in MECP2 has not been reported. But in ClinVar and gnomAD, the c.879C>G (p.Ile293Met) allele (rs587783140) is extremely rare in east Asian (MAF: 0.0002692) and Latino (MAF: 0.00007129), and is previously marked as uncertain significance (VUS). However, it is predicted to be deleterious by several commonly used algorithms, such as MutationTaster, Polyphen2 and Proven. According to ACMG criteria, the c.879C>G (p.Ile293Met) missense mutation is predicted to be likely pathogenic based on the fact that it is a DNM and located in a mutational hot spot, and yet a critical and well-established functional domain. No additional DNMs or causal alleles, related to intellectual disability, microcephaly or psychomotor retardation in autosomal recessive or X-linked form, were identified from the patient in the trio-WES analysis.
Invitae	RCV001498800	SCV001703553	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2022-08-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444598	SCV002682624	uncertain significance	Inborn genetic diseases	2019-03-22	criteria provided, single submitter	clinical testing	The p.I293M variant (also known as c.879C>G), located in coding exon 3 of the MECP2 gene, results from a C to G substitution at nucleotide position 879. The isoleucine at codon 293 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV003975140	SCV004790992	likely benign	MECP2-related condition	2022-02-23	criteria provided, single submitter	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).