Submissions for variant NM_001110792.2(MECP2):c.47_57del (p.Gly16fs)

dbSNP: rs786205042

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000170288	SCV001250620	pathogenic	Rett syndrome		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245569	SCV001418865	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2022-02-03	criteria provided, single submitter	clinical testing	The MECP2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001110792.1, and corresponds to NM_004992.3:c.-114_-104del in the primary transcript. This sequence change creates a premature translational stop signal (p.Gly16Glufs*22) in the MECP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MECP2 are known to be pathogenic (PMID: 12180070). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 15857422, 16155192, 17968969, 22213695, 23810759). In at least one individual the variant was observed to be de novo. This variant is also known as c.38_48del11. ClinVar contains an entry for this variant (Variation ID: 189770). For these reasons, this variant has been classified as Pathogenic.
Centre for Population Genomics, CPG	RCV000170288	SCV004808737	pathogenic	Rett syndrome	2024-02-18	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: This variant has been identified as a de novo occurrence in>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). PMID: 15034579, 15689438 , 15857422, 17968969, 23810759 At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 15034579. This variant is absent from gnomAD (PM2_Supporting).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000170288	SCV005398008	pathogenic	Rett syndrome	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with MECP2-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability demonstrate X-linked recessive inheritance (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by two clinical diagnostic laboratories (ClinVar). This variant is also present in RettBASE as associated with disease and has been reported in multiple individuals with atypical Rett syndrome, classic Rett syndrome or epilepsy with autism spectrum disorder (Rettsyndrome.org; PMIDs: 15689438, 23810759, 31139143). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000170288	SCV000032844	pathogenic	Rett syndrome	2006-06-01	no assertion criteria provided	literature only
RettBASE	RCV000170288	SCV000222621	pathogenic	Rett syndrome	2013-12-05	no assertion criteria provided	curation