rs864309503

Variant names:

• chr22-30941503-G-A
• rs864309503
• NM_001303256.3:c.754C>T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001303256.3(MORC2):​c.754C>T​(p.Arg252Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:2
• Conservation: PhyloP100: 3.14

Genes affected

MORC2 (HGNC:23573): (MORC family CW-type zinc finger 2) This gene encodes a member of the Microrchidia (MORC) protein superfamily. The encoded protein is known to regulate the condensation of heterochromatin in response to DNA damage and play a role in repressing transcription. The protein has been found to regulate the activity of ATP citrate lyase via specific interaction with this enzyme in the cytosol of lipogenic breast cancer cells. The protein also plays a role in lipogenesis and adipocyte differentiation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MORC2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.2251 (above the threshold of 3.09). Trascript score misZ: 4.4393 (above the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, Charcot-Marie-Tooth disease axonal type 2Z, developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 22-30941503-G-A is Pathogenic according to our data. Variant chr22-30941503-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30941503-G-A is described in Lovd as [Likely_pathogenic]. Variant chr22-30941503-G-A is described in Lovd as [Pathogenic]. Variant chr22-30941503-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORC2	NM_001303256.3	c.754C>T	p.Arg252Trp	missense_variant	Exon 9 of 26	ENST00000397641.8	NP_001290185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MORC2	ENST00000397641.8	c.754C>T	p.Arg252Trp	missense_variant	Exon 9 of 26	5	NM_001303256.3	ENSP00000380763.2
MORC2	ENST00000215862.8	c.568C>T	p.Arg190Trp	missense_variant	Exon 10 of 27	1		ENSP00000215862.4
MORC2	ENST00000469915.1	n.308C>T		non_coding_transcript_exon_variant	Exon 3 of 6	3
MORC2	ENST00000675601.1	n.596C>T		non_coding_transcript_exon_variant	Exon 5 of 22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z Pathogenic:10

Jul 20, 2021

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 24, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 22, 2024

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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/. -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 21, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Functional Genomics, Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vivo

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. -

Apr 25, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM2, PP3, PS3, PP5; Variant was found in heterozygous state -

not provided Pathogenic:2

Apr 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Apr 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 10, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy Pathogenic:1

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Charcot-Marie-Tooth disease Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Distal spinal muscular atrophy Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.046	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.051	T;T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.57		Loss of sheet (P = 0.0037);.;
MVP		0.76
MPC		2.1
ClinPred		0.97	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.65
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864309503; hg19: chr22-31337490; COSMIC: COSV53196061; COSMIC: COSV53196061;