Submissions for variant NM_001110792.2(MECP2):c.1366G>A (p.Ala456Thr)

gnomAD frequency: 0.00080  dbSNP: rs61753975

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081198	SCV000113106	benign	not specified	2013-12-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000081198	SCV000170235	benign	not specified	2013-10-03	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	RCV000081198	SCV000193630	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224116	SCV000281659	benign	not provided	2015-12-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082471	SCV000645660	benign	Severe neonatal-onset encephalopathy with microcephaly	2024-01-29	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659843	SCV000781716	likely benign	Rett syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000081198	SCV000919616	benign	not specified	2018-03-27	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.1330G>A (p.Ala444Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 200146 control chromosomes in the gnomAD database, including 55 hemizygotes. The observed variant frequency is approximately 118.11 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 benign. To our knowledge, no experimental evidence demonstrating the impact on protein function of c.1330G>A have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000659843	SCV001142077	benign	Rett syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224116	SCV001150509	likely benign	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV000659843	SCV004098739	benign	Rett syndrome	2023-08-14	criteria provided, single submitter	curation	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria.Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2, PMID: 11738860, PMID: 11055898). This variant did not segregate in a similarly affected family member (BS4_Supporting, PMID: 11738860)
RettBASE	RCV000081198	SCV000187976	benign	not specified	2010-05-14	no assertion criteria provided	curation
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000224116	SCV000804264	benign	not provided	2015-04-03	no assertion criteria provided	clinical testing