rs864309504

Variant names:

• chr22-30949809-G-A
• rs864309504
• NM_001303256.3:c.260C>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.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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MORC2 NM_001303256.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 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 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, 0.865
• 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 rank	MANE	Protein	UniProt
MORC2	NM_001303256.3	c.260C>T	p.Ser87Leu	missense_variant	Exon 5 of 26	ENST00000397641.8	NP_001290185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MORC2	ENST00000397641.8	c.260C>T	p.Ser87Leu	missense_variant	Exon 5 of 26	5	NM_001303256.3	ENSP00000380763.2
MORC2	ENST00000215862.8	c.74C>T	p.Ser25Leu	missense_variant	Exon 6 of 27	1		ENSP00000215862.4
MORC2	ENST00000476152.2	n.382C>T		non_coding_transcript_exon_variant	Exon 4 of 7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.260C>T(p.Ser87Leu) variant in MORC2 gene has been reported previously in multiple individuals affected with Charcot-Marie-Tooth disease (Duan X, et al., 2021; Guillen Sacoto MJ, et al., 2020; Hyun YS, et al., 2016). Functional studies indicate that this variant significantly reduces MORC2 ATPase activity and demonstrates a damaging effect (Sancho P, et al., 2019; Douse CH, et al., 2018). The p.Ser87Leu variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Pathogenic (multiple submissions). The amino acid change p.Ser87Leu in MORC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 87 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Oct 24, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Global developmental delay Pathogenic:1

Nov 01, 2019

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Inborn genetic diseases Pathogenic:1

Jul 19, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:1

Jan 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 29440755); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34189813, 26497905, 27105897, 28135719, 31211173, 30624633, 32693025, 34059105, 31785789, 33762496, 29440755) -

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

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Laboratory of Functional Genomics, Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

Variant c.260C>T in MORC2 was found in a Patient with clinical signs of DIFGAN syndrome. Segregation analysis confirmed its de novo. This variant is absent in population databases. 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 significant reduction of MORC2 protein quantity compared to wt vector. In summary, c.260C>T variant meets criteria to be classified as pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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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;.
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;