Submissions for variant NM_001110792.2(MECP2):c.771C>G (p.Val257=)

gnomAD frequency: 0.00013  dbSNP: rs782027467

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457731	SCV000556751	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781522	SCV000919621	benign	not specified	2018-09-04	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.735C>G alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: five predict the variant strengthens a cryptic 5 prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 178616 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.00087 in the gnomAD database. This frequency within Latino control individuals is approximately 104-fold above 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 a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.735C>G in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001672782	SCV001888343	benign	not provided	2018-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002383867	SCV002674981	likely benign	Inborn genetic diseases	2018-12-31	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	RCV004535444	SCV004740020	likely benign	MECP2-related disorder	2022-01-03	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).