Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000193537 | SCV003853559 | pathogenic | Rett syndrome | 2021-12-13 | reviewed by expert panel | curation | The p.Arg167Trp variant (NM_004992.3) in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with MECP2-related disorders through testing completed at GeneDx (PS2_very strong). The variant has been reported to segregate in at least five informative meioses in published literature (Couvert et al., 2001) (PP1_strong). The p.Arg167Trp variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg167Trp variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PP1_strong, PM2_supporting). |
Genetic Services Laboratory, |
RCV000193537 | SCV000247973 | pathogenic | Rett syndrome | 2013-02-08 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000498300 | SCV000589567 | pathogenic | not provided | 2021-12-03 | criteria provided, single submitter | clinical testing | Heterozygous carrier females with resting tremors have been reported (Gomot et al., 2003).; Functional studies show the R167W mutant protein is defective, as when expressed in mouse myoblast cells, chromocenter clustering reduced in size and increased in number (Sheikh et al., 2016).; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30083362, 26490184, 11309367, 27929079, 14598336, 26350204, 27323888, 30536762) |
Invitae | RCV000688107 | SCV000815707 | pathogenic | Severe neonatal-onset encephalopathy with microcephaly | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the MECP2 protein (p.Arg167Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MECP2-related conditions (PMID: 11309367, 14598336, 26350204, 26490184, 27929079, 30083362). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143603). 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) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MECP2 function (PMID: 27929079). For these reasons, this variant has been classified as Pathogenic. |
Génétique des Maladies du Développement, |
RCV000193537 | SCV001164193 | uncertain significance | Rett syndrome | 2017-11-27 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000498300 | SCV001246090 | pathogenic | not provided | 2019-04-01 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Applied Genomics, |
RCV000498300 | SCV001447614 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Laboratorio de Genetica e Diagnostico Molecular, |
RCV002252000 | SCV002523239 | pathogenic | See cases | 2019-09-16 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS3, PS4, PM2, PP3 |
Ambry Genetics | RCV002336285 | SCV002640663 | pathogenic | Inborn genetic diseases | 2019-04-26 | criteria provided, single submitter | clinical testing | The p.R167W pathogenic mutation (also known as c.499C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 499. The arginine at codon 167 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation segregated with disease in four affected males over two generations within a large family and was absent in a healthy maternally related male (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6). Affected males in this family were noted to have moderate intellectual disability, microcephaly, seizures, hypoactivity, poor coordination, brisk tendon reflexes, difficulties with written language, verbal stereotypies, and resting tremors, which were also observed in two obligate carrier females (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6; Gomot M et al. Am. J. Med. Genet. A, 2003 Dec;123A:129-39). In another family, this mutation was detected in 3 affected brothers and their mother, who demonstrated skewed X-inactivation (Bianciardi L et al. J. Hum. Genet., 2016 Feb;61:95-101). C2C12 cells expressing this mutation demonstrated an increased number of chromocenters with decreased size (Sheikh TI et al. Sci Rep, 2016 12;6:38590). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Athena Diagnostics Inc | RCV000498300 | SCV002770825 | pathogenic | not provided | 2022-09-15 | criteria provided, single submitter | clinical testing | This variant has been reported in multiple male individuals with an X-linked intellectual developmental disorder. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function shows this variant causes a chromatin binding defect, increasing the number of chromocenters and decreasing their size (PMID: 27929079). Further research is needed to determine disease consequence. This variant segregates with disease in multiple families. |
Eurofins- |
RCV000133142 | SCV003935091 | pathogenic | X-linked intellectual disability-psychosis-macroorchidism syndrome | 2022-11-23 | criteria provided, single submitter | clinical testing | |
Rett |
RCV000133142 | SCV000188134 | uncertain significance | X-linked intellectual disability-psychosis-macroorchidism syndrome | 2011-02-15 | no assertion criteria provided | curation | |
Genome Diagnostics Laboratory, |
RCV000498300 | SCV001931110 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000498300 | SCV001972154 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000498300 | SCV002037458 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |