ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs61751445
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Total submissions: 11
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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)
Invitae RCV001089108 SCV000766874 likely benign Severe neonatal-onset encephalopathy with microcephaly 2021-10-27 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000712288 SCV000842741 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000719524 SCV000850392 likely benign History of neurodevelopmental disorder 2018-07-25 criteria provided, single submitter clinical testing Does not segregate in family study ;Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
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

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