Submissions for variant NM_001303256.3(MORC2):c.260C>T (p.Ser87Leu)

dbSNP: rs864309504

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522454	SCV000618293	pathogenic	not provided	2019-08-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Douse et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26497905, 27105897, 29440755, 28135719, 31211173, 30624633, 32693025)
Invitae	RCV000202460	SCV000655836	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2023-08-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 218308). 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. This variant is not present in population databases (gnomAD no frequency). 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).
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001255406	SCV001431806	pathogenic	Global developmental delay	2019-11-01	criteria provided, single submitter	clinical testing
3billion	RCV000202460	SCV002012146	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least two similarly affected unrelated individuals (PMID:26497905, 27105897, PS2, PS4_M). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.816, 3Cnet: 0.757, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000202460	SCV004101531	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z		criteria provided, single submitter	clinical testing	The missense variant c.260C>T (p.Ser87Leu) in the MORC2 gene has been reported in heterozygous state in individuals affected with Charcot-Marie-Tooth disease type 2Z (Hyun YS. et al., 2016). Experimental studies have shown that this missense has a damaging effect on the protein (Douse CH. et al., 2018). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The amino acid Serine at position 87 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser87Leu in MORC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000202460	SCV000257500	pathogenic	Charcot-Marie-Tooth disease axonal type 2Z	2015-10-24	no assertion criteria provided	literature only
Genesis Genome Database	RCV000857126	SCV000999704	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research