Submissions for variant NM_001110792.2(MECP2):c.1042C>G (p.Leu348Val)

dbSNP: rs587783104

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001800461	SCV002047345	benign	Rett syndrome	2024-08-30	reviewed by expert panel	curation	The highest population minor allele frequency of the p.Leu336Val variant in MECP2 (NM_004992.4) in gnomAD v4.1 is 0.001148 in the Middle Eastern population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Leu336Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Leu336Val variant is found in at least 3 patients with an alternate molecular basis of disease (internal database) (BP5_Strong). In summary, the p.Leu336Val variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP5_Strong). (MECP2 specification v3.0.0; curation approved on 8/30/2024)
GeneDx	RCV000144771	SCV000190990	uncertain significance	not provided	2016-06-30	criteria provided, single submitter	clinical testing	The L336V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L336V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across mammals but not in distantly related species. 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 mutation or a rare benign variant.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000144771	SCV000221647	likely pathogenic	not provided		criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000144771	SCV003810854	uncertain significance	not provided	2021-02-25	criteria provided, single submitter	clinical testing