Submissions for variant NM_001303256.3(MORC2):c.754C>T (p.Arg252Trp)

dbSNP: rs864309503

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000202547	SCV000655834	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2024-06-22	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 252 of the MORC2 protein (p.Arg252Trp). 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, 26659848, 26912637, 27105987). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg190Trp. ClinVar contains an entry for this variant (Variation ID: 218307). 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 MORC2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000624201	SCV000742292	pathogenic	Inborn genetic diseases	2017-03-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000202547	SCV001141405	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091566	SCV001247691	pathogenic	not provided	2017-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001091566	SCV001786107	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging, gain-of-function effect (Tchasovnikarova et al., 2017; Douse et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26497905, 31372974, 27794525, 29440755, 28402445, 28334961, 7964809, 12601114, 27105987, 26659848, 27105897, 28251916, 28771897, 27329773, 30624633, 34059105, 33333791, 26912637, 28581500)
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	RCV000202547	SCV001934607	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2021-07-20	criteria provided, single submitter	research	The p.Arg252Trp variant in the MORC2 gene has been reported in several families with Charcot-Marie-Tooth disease, type 2Z (AD-CMT2Z; OMIM: 616688). This variant is considered a hotspot, and most patients are sporadic cases (PMID: 30624633). This variant is also known as p.Arg190Trp in the literature. This variant is not present in population databases (GnomAD and ABraOM). ClinVar classifies this variant as Pathogenic (Variation ID: 218307), 2 stars (multiple consistent, 9 submissions), backed by functional studies (requires user validation) mentioned in 30624633, and also citing 10 articles (29440755, 28771897, 28581500, 27105987, 27105897 and 5 more). These amino acids are located in an important and highly conserved functional domain of the protein (GHKL-type ATPase). In summary, the p.Arg252Trp meets our criteria to be classified as pathogenic.
3billion, Medical Genetics	RCV000202547	SCV003841875	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.67). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000218307). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28771897). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV003387804	SCV003920783	pathogenic	Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy	2023-04-27	criteria provided, single submitter	research
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV000202547	SCV003930346	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2024-05-22	criteria provided, single submitter	research	PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PP2 met: missense Z-score is 3.23. PP1_strong: variant segregates with =5 informative meioses across =1 family. PP3 met: REVEL score is 0.70. PM1 met: variant occurs in the GHKL-type ATPase domain together with other pathogenic variants. PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product (PMID: 29440755, 28581500). PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000202547	SCV004015113	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2023-07-21	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV000202547	SCV005043005	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2024-04-25	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2, PP3, PS3, PP5; Variant was found in heterozygous state
Laboratory of Functional Genomics, Research Centre for Medical Genetics	RCV000202547	SCV005626395	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z		criteria provided, single submitter	clinical testing	Variant c.754C>T in MORC2 was found in a patient with clinical signs of Charcot–Marie–Tooth disease. Segregation analysis was not performed. This variant is absent in population databases. Additionally, it was described in other groups of patients with Charcot–Marie–Tooth disease (doi: 10.1093/brain/awv411, doi: 10.1093/brain/awv311). 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 slight reduction of MORC2 protein quantity compared to wt vector. In summary, c.754C>T variant meets criteria to be classified as pathogenic.
OMIM	RCV000202547	SCV000257499	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2015-10-24	no assertion criteria provided	literature only
Genesis Genome Database	RCV000857122	SCV000999700	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research
Genesis Genome Database	RCV000857123	SCV000999701	uncertain significance	Distal spinal muscular atrophy	2019-08-14	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000202547	SCV001760485	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2Z		no assertion criteria provided	clinical testing