ClinVar Miner

Submissions for variant NM_001110792.2(MECP2):c.1165_1234del (p.Lys389fs)

dbSNP: rs1557135353
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel RCV000590874 SCV002569942 uncertain significance Rett syndrome 2022-07-21 reviewed by expert panel curation The c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_supporting). The p.(Lys377ProfsTer9) variant in MECP2 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.(Lys377ProfsTer9) variant has been reported in 1 individual with an epilepsy and neurodevelopmental disorder (PMID 29655203), and 1 individual with developmental delay and autism where it was inherited from a mother with a history of learning difficulties (ClinVar SCV000190972.2) (PS4_Supporting has not been applied as it is unclear whether these citations reflect two independent occurrences). The p.(Lys377ProfsTer9) variant has also been found in a patient with an alternate molecular basis of disease (PMID 29961512). This patient had early infantile epileptic encephalopathy, however did not meet the diagnostic criteria for either typical or atypical Rett. The p.(Lys377ProfsTer9) variant was found to be inherited from this patient's father, who was reported as having a history of seizures as a child and learning disability but was otherwise described as unaffected (BS2_Supporting). Furthermore, this patient was also found to be heterozygous for a de novo (biological parentage confirmed) GNAO1 missense variant that was deemed to be causative of this patient's clinical presentation (BP5). In summary, the c.1129_1198del p.(Lys377ProfsTer9) variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PVS1, PM2_supporting, BP5, BS2_Supporting).
GeneDx RCV000144758 SCV000190972 pathogenic not provided 2013-12-11 criteria provided, single submitter clinical testing The c.1129_1198del70 mutation results in a deletion of 70 base pairs located in the deletion-prone region at the 3' end of the MECP2 gene. This deletion causes a frameshift starting with codon Lysine 377, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Lys377ProfsX9. This deletion results in the replacement of the last 110 amino acids of the protein with 8 aberrant amino acids and is predicted to cause loss of normal protein function through protein truncation. This mutation has not been reported previously to our knowledge, although large deletions in this region of the gene have been identified in patients with classic and atypical Rett syndrome. The variant is found in INFANT-EPI panel(s).
Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN) RCV000590874 SCV000700176 benign Rett syndrome criteria provided, single submitter clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine RCV003126509 SCV003803868 likely pathogenic X-linked intellectual disability-psychosis-macroorchidism syndrome 2022-06-29 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.