Submissions for variant NM_001110792.2(MECP2):c.1120C>T (p.Pro374Ser)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV003448314	SCV004175923	likely benign	Rett syndrome	2023-10-13	reviewed by expert panel	curation	The p.Pro362Ser variant in MECP2 (NM_004992.3) is present in 1 XX and 1 XY individual in gnomAD (0.0011%) (not sufficient to meet BS1 criteria). The p.Pro362Ser variant in MECP2 is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro362Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2).
GeneDx	RCV000493837	SCV000581980	uncertain significance	not provided	2017-04-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MECP2 gene. The P362S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P362S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P362S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257760	SCV001434572	likely benign	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001312686	SCV001503150	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2023-09-08	criteria provided, single submitter	clinical testing

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