Submissions for variant NM_001110792.2(MECP2):c.1096C>T (p.Arg366Cys)

gnomAD frequency: 0.00007  dbSNP: rs143876280

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	RCV002472366	SCV002769738	benign	Rett syndrome	2022-12-09	reviewed by expert panel	curation	The allele frequency of the p.Arg354Cys variant in MECP2 (NM_004992.3) is 0.028% in East Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Arg354Cys variant is observed in at least 2 unaffected individuals (internal database) (BS2). In summary, the p.Arg354Cys variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2).
Eurofins Ntd Llc (ga)	RCV000724672	SCV000230275	uncertain significance	not provided	2015-04-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000193184	SCV000247924	likely benign	not specified	2013-12-20	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000193184	SCV000537172	uncertain significance	not specified	2015-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV001432219	SCV001634983	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2023-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000724672	SCV001767171	likely benign	not provided	2021-03-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000724672	SCV001549160	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MECP2 p.R354C variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs143876280), LOVD 3.0 and ClinVar (classified as conflicting interpretations of pathogenicity with University of Chicago Genetic Services Laboratory classifying the variant as likely benign and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children and EGL Genetics classifying the variant as uncertain significance). The variant was identified in control databases in 5 of 182156 chromosomes (0 homozygous; 2 hemizygous) at a frequency of 0.000027 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 5 of 81121 chromosomes (freq: 0.00006), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Arg354 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.