rs864309504

chr22-30949809-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001303256.3(MORC2):c.260C>T(p.Ser87Leu) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S87P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 9.60

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 17 ACMG points.

• PM1: In a binding_site (size 2) in uniprot entity MORC2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001303256.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-30949810-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1699240.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, MORC2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 22-30949809-G-A is Pathogenic according to our data. Variant chr22-30949809-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30949809-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MORC2	NM_001303256.3	c.260C>T	p.Ser87Leu	missense_variant	5/26	ENST00000397641.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MORC2	ENST00000397641.8	c.260C>T	p.Ser87Leu	missense_variant	5/26	5	NM_001303256.3	P1
MORC2	ENST00000215862.8	c.74C>T	p.Ser25Leu	missense_variant	6/27	1
MORC2	ENST00000476152.2	n.382C>T		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 24, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 25, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Nov 01, 2019

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2019

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) -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.027	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.57		Loss of disorder (P = 0.0123);.;
MVP		0.65
MPC		1.2
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.92

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: rs864309504; hg19: chr22-31345795; COSMIC: COSV53196098;