Submissions for variant NM_001110792.2(MECP2):c.710C>G (p.Pro237Arg)

dbSNP: rs61749715

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476280	SCV000544623	pathogenic	Severe neonatal-onset encephalopathy with microcephaly	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 225 of the MECP2 protein (p.Pro225Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with either classic or atypical Rett syndrome (PMID: 10767337, 10854091, 11524741, 12075485, 12111643, 16473305, 16690727, 17142618). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MECP2 protein function. This variant disrupts the p.Pro225 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12615169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626873	SCV000747576	pathogenic	Seizure; Absent speech; Developmental regression; Severe global developmental delay; Irregular respiration	2017-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090502	SCV001246088	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001090502	SCV001449032	pathogenic	not provided	2016-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001090502	SCV001813722	pathogenic	not provided	2020-01-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Guy et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33084218, 10854091, 17089071, 10805343, 17387578, 21160487, 26984561, 11245712, 22190343, 26469135, 22139899, 15880509, 18056689, 19133691, 11524741, 29782864, 12180070, 18842453, 21954873, 12655490, 11214906, 12746405, 15675358, 29718204, 17142618, 16690727, 16473305, 12111643, 12075485, 10767337)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000133193	SCV004013295	pathogenic	Rett syndrome	2023-06-14	criteria provided, single submitter	clinical testing	PS2, PS3, PS4, PM2, PP3
Centre for Population Genomics, CPG	RCV000133193	SCV004808878	pathogenic	Rett syndrome	2024-03-22	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 pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong).(PMID: 17089071, 10767337). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 31427717, 17407838, 17387578, 17089071, 16473305, 19133691, 18842453, 10767337, 11245712). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD v4 (PM2_Supporting).
RettBASE	RCV000133193	SCV000188191	pathogenic	Rett syndrome	2012-05-18	no assertion criteria provided	curation
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000133193	SCV001427577	likely pathogenic	Rett syndrome	2019-01-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532609	SCV004745606	pathogenic	MECP2-related disorder	2024-08-08	no assertion criteria provided	clinical testing	The MECP2 c.674C>G variant is predicted to result in the amino acid substitution p.Pro225Arg. This variant was reported in multiple individuals with Rett syndrome, epilepsy or intellectual disability and has been described as a recurrent causative variant documented as de novo in at least one patient (Cheadle et al. 2000. PubMed ID: 10767337; Table S2, Truty et al. 2019. PubMed ID: 31440721; Table S2, Dong et al. 2020. PubMed ID: 32005694; Table S1, Wen et al. 2020. PubMed ID: 32472557). In vitro functional studies found this variant interferes with protein function through decreased stability or conformational changes (Guy et al. 2018. PubMed ID: 29718204). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.