Submissions for variant NM_001110792.2(MECP2):c.289C>T (p.Arg97Cys)

gnomAD frequency: 0.00001  dbSNP: rs1064797047

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001775123	SCV002769729	uncertain significance	Rett syndrome	2022-12-08	reviewed by expert panel	curation	The p.Arg85Cys variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in one individual (3billion) (PM6). The p.Arg85Cys variant in MECP2 (NM_004992.3) is found in a patient with an alternate molecular basis of disease (internal database) (BP5). The p.Arg85Cys variant in MECP2 (NM_004992.3) is observed in 1 unaffected individuals (internal database) (BS2_supporting). Computational prediction analysis tools are inconclusive for this variant. In summary, the p.Arg85Cys variant in MECP2 (NM_004992.3) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM6, BP5, BS2_supporting).
GeneDx	RCV000487257	SCV000574400	uncertain significance	not provided	2020-01-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously reported as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25927341)
3billion	RCV001775123	SCV002012117	likely pathogenic	Rett syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000985267.2, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00000546, PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525978	SCV003009211	benign	Severe neonatal-onset encephalopathy with microcephaly	2022-08-16	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV001775123	SCV005687680	uncertain significance	Rett syndrome	2024-12-02	criteria provided, single submitter	curation	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 Uncertain significance - conflicting evidence. The following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting) (ClinVar Accession: SCV002769729.1 Rett and Angelman-like Disorders VCEP internal database). Variant is found in an individual with an alternate molecular basis of disease (BP5) (ClinVar Accession: SCV002769729.1 Rett and Angelman-like Disorders VCEP internal database). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6) (ClinVar Accession: SCV002012117.1).