Submissions for variant NM_001110792.2(MECP2):c.1250C>T (p.Pro417Leu)

gnomAD frequency: 0.00004  dbSNP: rs61753016

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000225647	SCV002047361	benign	Rett syndrome	2021-12-22	reviewed by expert panel	curation	The allele frequency of the p.Pro405Leu (NM_004992.3) variant in MECP2 is 0.029% in Latino 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.Pro405Leu variant is observed in at least 2 unaffected individuals (GeneDx internal database)(BS2). In summary, the p.Pro405Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2).
GeneDx	RCV000132964	SCV000190998	uncertain significance	not provided	2018-02-02	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MECP2 gene. The P405L variant has been reported previously as a de novo variant in the hemizygous state in an individual with cognitive impairment, ADHD, and stereotypic hand movements (Campos et al., 2009). The P405L variant has also been reported previously in the hemizygous state in an individual with cognitive impairment, epilepsy, autism, and stereotypic hand movements; whose mother and sister with borderline intelligence were found to be heterozyous for the variant (Moog et al., 2006). The P405L variant is observed in 8/27147 (0.03%) alleles from individuals of Latino background, including 2 unrelated hemizygous individuals in large population cohorts (Lek et al., 2016). The P405L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000225647	SCV000282503	uncertain significance	Rett syndrome	2015-07-29	criteria provided, single submitter	clinical testing	c.1214C>T (p.Pro405Leu) is a missense mutation that occurs at a conserved position, and 4/4 in silico tools predict a damaging outcome. Pro405 is a highly conserved amino acid in the carboxy terminal domain, which affects the binding of MECP2 to DNA. However, functional studies have not been carried out to determine the functional impact of this change. The variant has been observed in 1 hemizygous male control from the ExAC cohort, suggesting this variant could be low penetrance, benign, or a mild mutation. The variant has also been cited in at least 2 male intellectually disabled patients (1 de novo occurrence with no family history of ID and 1 maternally inherited with borderline intelligence on both sides of the family). Taken together, the c.1214C>T variant in MECP2 is classified as a variant of uncertain significance (VUS) until additional functional or co-segregation studies are available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001004759	SCV000556755	likely benign	Severe neonatal-onset encephalopathy with microcephaly	2024-11-28	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004759	SCV001164239	uncertain significance	Severe neonatal-onset encephalopathy with microcephaly	2016-05-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000132964	SCV001246081	uncertain significance	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000132964	SCV001715427	uncertain significance	not provided	2020-07-17	criteria provided, single submitter	clinical testing
Centre for Population Genomics, CPG	RCV000225647	SCV004809001	benign	Rett syndrome	2024-03-14	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 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1).
RettBASE	RCV000169944	SCV000187948	uncertain significance	X-linked intellectual disability-psychosis-macroorchidism syndrome	2010-03-10	no assertion criteria provided	curation
PreventionGenetics, part of Exact Sciences	RCV004532596	SCV004735297	likely benign	MECP2-related disorder	2022-07-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).