Submissions for variant NM_001110792.2(MECP2):c.1171_1178del (p.Pro391fs)

dbSNP: rs267608571

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494344	SCV000582686	pathogenic	not provided	2024-08-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15558314)
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000851500	SCV000994555	pathogenic	Intellectual disability	2017-08-29	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000494344	SCV001447619	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003388830	SCV004100721	pathogenic	Rett syndrome	2023-08-31	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP,PS2_MOD
Centre for Population Genomics, CPG	RCV003388830	SCV004232330	pathogenic	Rett syndrome	2024-01-12	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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). Clinvar Variation ID: 143342, PMID 15558314 This variant is absent from gnomAD (PM2_Supporting).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003522929	SCV004299161	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro379Thrfs*11) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 15558314). ClinVar contains an entry for this variant (Variation ID: 143342). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Gln437Alafs*49) have been determined to be pathogenic (PMID: 11055898; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
RettBASE	RCV000132867	SCV000187847	pathogenic	X-linked intellectual disability-psychosis-macroorchidism syndrome	2005-11-18	no assertion criteria provided	curation