rs864309503

Positions:

• chr22-30941503-G-A

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:13 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 gene, where missense usually causes diseases (based on misZ statistic), MORC2. . Gene score misZ 3.2251 (greater than the threshold 3.09). Trascript score misZ 4.4393 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
MORC2	NM_001303256.3	c.754C>T	p.Arg252Trp	missense_variant	9/26	ENST00000397641.8	NP_001290185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MORC2	ENST00000397641.8	c.754C>T	p.Arg252Trp	missense_variant	9/26	5	NM_001303256.3	ENSP00000380763	P1
MORC2	ENST00000215862.8	c.568C>T	p.Arg190Trp	missense_variant	10/27	1		ENSP00000215862
MORC2	ENST00000469915.1	n.308C>T		non_coding_transcript_exon_variant	3/6	3
MORC2	ENST00000675601.1	n.596C>T		non_coding_transcript_exon_variant	5/22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z Pathogenic:9

Pathogenic, criteria provided, single submitter	research	Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	Jul 20, 2021	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 24, 2015	- -
Pathogenic, criteria provided, single submitter	research	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	May 22, 2024	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/. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jul 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Apr 25, 2024	ACMG Criteria: PM2, PP3, PS3, PP5; Variant was found in heterozygous state -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 2023	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 not present in population databases (gnomAD no frequency). 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 also known as p.Arg190Trp. ClinVar contains an entry for this variant (Variation ID: 218307). 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2017

- -

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

Pathogenic, criteria provided, single submitter

research

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Apr 27, 2023

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

- -

Distal spinal muscular atrophy Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

- -

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;.
MutationTaster	Benign	1.0	D;D
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;