Submissions for variant NM_001110792.2(MECP2):c.968C>T (p.Thr323Met)

gnomAD frequency: 0.00003  dbSNP: rs61751445

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000030168	SCV002540687	benign	Rett syndrome	2022-02-19	reviewed by expert panel	curation	The allele frequency of the p.Thr311Met variant in MECP2 (NM_004992.3) is 0.022% and 0.01% in "Other" and South Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Thr311Met variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2) and found in 2 patients with an alternate molecular basis of disease (Baylor Genetics internal database, Invitae internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). As this variant meets 2 strong and 1 supporting benign criteria it can be classified as benign even though in silico predictions meet PP3. In summary, the p.Thr311Met variant in MECP2 is classified as benign for Rett syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426076	SCV000052826	likely benign	not specified	2018-05-30	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.932C>T (p.Thr311Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 178987 control chromosomes including 2 hemizygotes (gnomAD). The observed variant frequency is approximately 4.7 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. The variant, c.932C>T, has been reported in the literature in one individual affected with Rett Syndrome (Kim_2006). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000712288	SCV000513565	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22277191, 16672765, 28250423)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001089108	SCV000766874	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2024-10-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712288	SCV000842741	uncertain significance	not provided	2018-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316203	SCV000850392	likely benign	Inborn genetic diseases	2018-07-25	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.
Centre for Population Genomics, CPG	RCV000030168	SCV004232260	likely benign	Rett syndrome	2024-01-09	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 3.0, this variant is classified as likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). Variant is found in an individual with an alternate molecular basis of disease (BP5). (ClinVar Variation ID:36496) The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3).
RettBASE	RCV000133294	SCV000188303	uncertain significance	X-linked intellectual disability-psychosis-macroorchidism syndrome	2012-09-27	no assertion criteria provided	curation
RettBASE	RCV000030168	SCV000222573	uncertain significance	Rett syndrome	2012-09-27	no assertion criteria provided	curation
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000712288	SCV001926570	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000712288	SCV001959064	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000426076	SCV001967667	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541029	SCV004782330	likely benign	MECP2-related disorder	2022-08-03	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).