Submissions for variant NM_001110792.2(MECP2):c.1469G>A (p.Arg490Gln)

gnomAD frequency: 0.00005  dbSNP: rs145790362

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV002260620	SCV002540688	likely benign	Rett syndrome	2022-02-18	reviewed by expert panel	curation	The p.Arg478Gln variant in MECP2 (NM_004992.3) is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). The p.Arg478Gln variant is found in a patient with an alternate molecular basis of disease (Invitae internal database) (BP5). In summary, the p.Arg478Gln variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5).
GeneDx	RCV000767162	SCV000191002	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing	The Arg478Gln missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged Glutamine residue, and it alters a highly conserved position in the C-terminal domain of the MECP2 protein. However, missense substitutions at nearby codons are classified as benign variants, suggesting that this region of the protein is tolerant of missense changes. Several in silico algorithms predict that Arg478Gln is likely benign, although another model suggests it may be damaging to protein structure/function. Therefore, based on the available information it is currently unclear whether Arg478Gln is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Fulgent Genetics, Fulgent Genetics	RCV000766080	SCV000897555	uncertain significance	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	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048888	SCV001212916	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 478 of the MECP2 protein (p.Arg478Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 156636). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003162601	SCV003904195	uncertain significance	Inborn genetic diseases	2023-06-20	criteria provided, single submitter	clinical testing	The c.1433G>A (p.R478Q) alteration is located in exon 4 (coding exon 3) of the MECP2 gene. This alteration results from a G to A substitution at nucleotide position 1433, causing the arginine (R) at amino acid position 478 to be replaced by a glutamine (Q)._x000D_ _x000D_ _x000D_ _x000D_ This variant is unlikely to be causative of Rett syndrome or MECP2 duplication syndrome; however, its contribution to the development of MECP2-related neurodevelopmental disorder is uncertain. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/205192) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.005% (1/18605) of European (Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Centre for Population Genomics, CPG	RCV002260620	SCV004098754	likely benign	Rett syndrome	2023-08-14	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 2.0, this variant is classified as Likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD V3 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).
RettBASE	RCV000170088	SCV000222404	benign	not specified	2013-12-05	no assertion criteria provided	curation