Submissions for variant NM_001110792.2(MECP2):c.1190C>A (p.Pro397His)

gnomAD frequency: 0.00004  dbSNP: rs111302745

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000193703	SCV000190994	likely benign	not specified	2016-06-30	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.
Genetic Services Laboratory, University of Chicago	RCV000193703	SCV000247930	likely benign	not specified	2014-03-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465490	SCV000556732	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2024-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193703	SCV005039464	likely benign	not specified	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.1154C>A (p.Pro385His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 1199903 control chromosomes and 18 hemizygotes (gnomAD database v4.0.0). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1154C>A in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 156631). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004948195	SCV005448953	likely benign	Inborn genetic diseases	2024-10-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV004532629	SCV004744685	likely benign	MECP2-related disorder	2022-03-24	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).