Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory of Functional Genomics, |
RCV005055008 | SCV005626388 | pathogenic | Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy | criteria provided, single submitter | clinical testing | Variant c.260C>T in MORC2 was found in a Patient with clinical signs of DIFGAN syndrome. Segregation analysis confirmed its de novo. This variant is absent in population databases. For functional characterization of the variant a vector, expressing MORC2 fused with Flag tag at C-terminal end, was created. Transfection of the plasmid into HEK293T cells followed by Western blotting revealed significant reduction of MORC2 protein quantity compared to wt vector. In summary, c.260C>T variant meets criteria to be classified as pathogenic. | |
| Neuberg Centre For Genomic Medicine, |
RCV000202460 | SCV004101531 | pathogenic | Charcot-Marie-Tooth disease axonal type 2Z | criteria provided, single submitter | clinical testing | The observed missense c.260C>T(p.Ser87Leu) variant in MORC2 gene has been reported previously in multiple individuals affected with Charcot-Marie-Tooth disease (Duan X, et al., 2021; Guillen Sacoto MJ, et al., 2020; Hyun YS, et al., 2016). Functional studies indicate that this variant significantly reduces MORC2 ATPase activity and demonstrates a damaging effect (Sancho P, et al., 2019; Douse CH, et al., 2018). The p.Ser87Leu variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Ser87Leu in MORC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 87 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. | |
| Ambry Genetics | RCV002433895 | SCV002745550 | pathogenic | Inborn genetic diseases | 2021-07-19 | criteria provided, single submitter | clinical testing | The p.S87L pathogenic mutation (also known as c.260C>T), located in coding exon 5 of the MORC2 gene, results from a C to T substitution at nucleotide position 260. The serine at codon 87 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected as de novo in multiple individuals with Charcot-Marie-Tooth disease type 2 (Hyun YS et al. Brain, 2016 07;139:e40; Sevilla T et al. Brain, 2016 Jan;139:62-72; Duan X et al. Orphanet J Rare Dis, 2021 05;16:244; Guillen Sacoto MJ et al. Am J Hum Genet, 2020 08;107:352-363). This alteration is located in the ATPase domain and is reported to result in reduced ATPase activity and abnormal N-terminal dimerization dynamics in human cell lines (Sancho P et al. Hum Mol Genet, 2019 05;28:1629-1644; Douse CH et al. Nat Commun, 2018 02;9:651). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| 3billion | RCV005055008 | SCV002012146 | pathogenic | Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy | 2024-09-03 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26497905, 27105897, 32693025). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.82 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000218308 /PMID: 26497905 /3billion dataset).The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 26497905, 27105897, 32693025).The variant has been observed in at least two similarly affected unrelated individuals (PMID: 26497905, 27105897, 32693025).A different missense change at the same codon (p.Ser87Pro) has been reported to be associated with MORC2 related disorder (ClinVar ID: VCV001699240). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Génétique des Maladies du Développement, |
RCV001255406 | SCV001431806 | pathogenic | Global developmental delay | 2019-11-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000202460 | SCV000655836 | pathogenic | Charcot-Marie-Tooth disease axonal type 2Z | 2025-10-02 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 87 of the MORC2 protein (p.Ser87Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 2 (CMT2) (PMID: 26497905, 27105897). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 218308). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MORC2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000522454 | SCV000618293 | pathogenic | not provided | 2024-01-29 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect (PMID: 29440755); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34189813, 26497905, 27105897, 28135719, 31211173, 30624633, 32693025, 34059105, 31785789, 33762496, 29440755) |
| Genesis Genome Database | RCV000857126 | SCV000999704 | uncertain significance | Charcot-Marie-Tooth disease | 2019-08-14 | no assertion criteria provided | research | |
| OMIM | RCV000202460 | SCV000257500 | pathogenic | Charcot-Marie-Tooth disease axonal type 2Z | 2015-10-24 | no assertion criteria provided | literature only |