Submissions for variant NM_001110792.2(MECP2):c.414-3C>G

dbSNP: rs267608465

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000170202	SCV001712046	pathogenic	Rett syndrome	2021-03-26	reviewed by expert panel	curation	The c.378-3C>G variant in MECP2 has been observed in at least 5 individuals with Angelman syndrome (PMID: 15737703, Rettbase, GeneDx internal data) (PS4). It has been reported in at least 2 unconfirmed de novo occurrences in individuals with Rett syndrome (PMID 15737703, 20142466) (PM6_strong). The c.378-3C>G variant in MECP2 is absent from gnomAD (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). In summary, the c.378-3C>G variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM6_strong, PM2_supporting, PP3).
GeneDx	RCV000144115	SCV000329582	likely pathogenic	not provided	2023-09-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 26254891, 25525159, 15737703, 20142466, 24508304, 30536762, 34619114)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000170202	SCV000917616	pathogenic	Rett syndrome	2023-10-20	criteria provided, single submitter	clinical testing	Variant summary: MECP2 c.378-3C>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes the canonical 3' acceptor site, while four predict the variant creates a 3' acceptor site two nucleotides upstream from the original site, which is predicted to cause a frameshift, if utilized. Since the variant is located at the last intron-exon junction, it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a large part of the 486 amino acids long protein (and likely replacing it with an incorrect sequence). However, these predictions have yet to be confirmed by functional studies. The variant was absent in 181290 control chromosomes (gnomAD). The variant, c.378-3C>G, has been reported in the literature in at least two affected individuals as a de novo occurrence, i.e. in one female with classical Rett syndrome (Fukuda_2005), and in one male in who had acquired (progressive) microcephaly, regression of milestones, mitochondrial dysfunction, and episodic rigidity (Condie_2010). In addition, the variant was also reported in another male affected with progressive encephalopathy (Neul_2019) and multiple females diagnosed with classical (or unspecified) Rett syndrome (e.g. Bisgaard_2015, Liu_2022, RettBase (PMID: 28544139)). These data indicate that the variant likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20142466, 15737703, 24508304, 30536762, 26254891, 26228846, 34619114). Ten other submitters, including an expert panel (ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel), have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=5; including the expert panel) / likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000170202	SCV000928393	likely pathogenic	Rett syndrome	2018-11-30	criteria provided, single submitter	clinical testing	PS2, PM2, PP4, PP5
Invitae	RCV000800164	SCV000939864	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-09-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the MECP2 gene. It does not directly change the encoded amino acid sequence of the MECP2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Rett syndrome (PMID: 15737703, 24508304, 30536762). In at least one individual the variant was observed to be de novo. This variant is also known as Ex4 acceptor site. ClinVar contains an entry for this variant (Variation ID: 156068). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000857	SCV001157932	pathogenic	not specified	2018-10-03	criteria provided, single submitter	clinical testing	The MECP2 c.378-3C>G variant (rs267608465), is reported in the literature in multiple females affected with classic Rett syndrome (Fukuda 2005, Kalman 2014), and also in a male affected with Rett syndrome (Condie 2010). This variant is reported as pathogenic in ClinVar (Variation ID: 156068), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 3, which is likely to disrupt gene function by creating a novel spice acceptor site that is predicted to cause a frameshift. Based on available information, the c.378-3C>G variant is considered to be pathogenic. References: Condie J et al. Acquired microcephaly, regression of milestones, mitochondrial dysfunction, and episodic rigidity in a 46,XY male with a de novo MECP2 gene mutation. J Child Neurol. 2010 May;25(5):633-6. Fukuda T et al. Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. Brain Dev. 2005 Apr;27(3):211-7. Kalman LV et al. Development of a genomic DNA reference material panel for Rett syndrome (MECP2-related disorders) genetic testing. J Mol Diagn. 2014 Mar;16(2):273-9.
Genetic Services Laboratory, University of Chicago	RCV000144115	SCV002069280	likely pathogenic	not provided	2018-10-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345450	SCV002622561	likely pathogenic	Inborn genetic diseases	2018-10-01	criteria provided, single submitter	clinical testing	The c.378-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 3 in the MECP2 gene.This alteration has been detected twice as de novo occurrences: once in a female with typical Rett syndrome (Fukuda T et al. Brain Dev., 2005 Apr;27:211-7) and once in a male with acquired microcephaly, increased muscle tone and reflexes, mitochondrial impairments, and regression (Condie J et al. J. Child Neurol., 2010 May;25:633-6). Additionally, this alteration was detected in two individuals with Rett syndrome; however no specific phenotypic information was provided (Kalman LV et al. J Mol Diagn, 2014 Mar;16:273-9; Krishnaraj R et al. Hum. Mutat., 2017 08;38:922-931). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP, ESEfinder, MaxEnt, and HSF splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV000170202	SCV003834882	pathogenic	Rett syndrome	2021-01-28	criteria provided, single submitter	clinical testing
3billion	RCV000170202	SCV003842079	pathogenic	Rett syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Intron variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 1.00). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15737703). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 15737703, 20142466). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000156068 / PMID: 15737703). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224800	SCV003920886	likely pathogenic	Severe neonatal-onset encephalopathy with microcephaly; Syndromic X-linked intellectual disability Lubs type; X-linked intellectual disability-psychosis-macroorchidism syndrome; Rett syndrome; Autism, susceptibility to, X-linked 3	2021-03-30	criteria provided, single submitter	clinical testing	MECP2 NM_004992.3 exon 4 c.378-3C>G p.?: This variant has been reported in the literature as de novo in one female with classic Rett syndrome, as well as in the RettBASE in two additional females with classic Rett syndrome (Fukuda 2005 PMID:15737703, Christodoulou 2003 PMID:12673788). This variant is not present in large control databases, and it is present in ClinVar (Variation ID:156068). Computational tools designed to predict splicing suggest an effect from this variant through creation of a new acceptor site. However, further studies are needed to understand its impact. Of note, the vast majority of pathogenic variants are identified in exon 4 of this gene, which encodes for the methyl binding domain and transcription repression domain; this intronic variant falls just outside of that region (Philippe 2006 PMID:16473305). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000144115	SCV004226285	pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing	PP3, PP5, PM2, PM6_strong, PS4_moderate
Centre for Population Genomics, CPG	RCV000170202	SCV004232272	pathogenic	Rett syndrome	2024-01-10	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 at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4).(PMID: 15737703, Variation ID:156068). This variant is absent from gnomAD (PM2_Supporting).
RettBASE	RCV000144115	SCV000189191	not provided	not provided		flagged submission	not provided
RettBASE	RCV000170202	SCV000222531	pathogenic	Rett syndrome	2008-02-18	no assertion criteria provided	curation