Submissions for variant NM_001110792.2(MECP2):c.1183C>T (p.Leu395Phe)

gnomAD frequency: 0.00001  dbSNP: rs1340029095

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV003448328	SCV004175921	likely benign	Rett syndrome	2023-12-06	reviewed by expert panel	curation	The p.Leu383Phe variant in MECP2 (NM_004992.4) is observed in at least 2 unaffected individuals (internal database - Invitae) (BS2). This variant is also found in two patients with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The p.Leu383Phe variant is present in 10 XX and 5 XY individuals in gnomAD v4 (0.001%) (not sufficient to meet BS1 criteria). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Leu395Phe variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5).
GeneDx	RCV000600874	SCV000728725	likely benign	not specified	2017-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000600874	SCV000919618	uncertain significance	not specified	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.1147C>T (p.Leu383Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-06 in 173283 control chromosomes including one female in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1147C>T in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210472	SCV001381961	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2024-01-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508974	SCV001715429	uncertain significance	not provided	2020-12-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004024999	SCV004903857	uncertain significance	Inborn genetic diseases	2024-02-13	criteria provided, single submitter	clinical testing	The c.1147C>T (p.L383F) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a C to T substitution at nucleotide position 1147, causing the leucine (L) at amino acid position 383 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004735674	SCV005355946	likely benign	MECP2-related disorder	2024-09-04	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).