rs1555938796

Variant names:

• chr22-30938098-T-C
• rs1555938796
• NM_001303256.3:c.1181A>G

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.1181A>G​(p.Tyr394Cys) 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 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:7
• Conservation: PhyloP100: 7.65

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, 0.899
• PP5: Variant 22-30938098-T-C is Pathogenic according to our data. Variant chr22-30938098-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30938098-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MORC2	NM_001303256.3	c.1181A>G	p.Tyr394Cys	missense_variant	Exon 13 of 26	ENST00000397641.8	NP_001290185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MORC2	ENST00000397641.8	c.1181A>G	p.Tyr394Cys	missense_variant	Exon 13 of 26	5	NM_001303256.3	ENSP00000380763.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2Z Pathogenic:3

Apr 18, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS2, PM2, PP3, PP5; Variant was found in heterozygous state. De novo-status was confirmed via in-house segregation analysis. -

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 394 of the MORC2 protein (p.Tyr394Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MORC2-related conditions (PMID: 28771897, 32693025). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 432089). 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. -

not provided Pathogenic:2

Sep 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 34189813, 28771897, 32693025, 33098801) -

Oct 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MORC2 c.1181A>G; p.Tyr394Cys variant (rs1555938796; ClinVar Variation ID: 432089), also known as NM_014941.3: p.Tyr332Cys, is reported in the literature in multiple individuals with MORC2-related neurodevelopmental disorders and is commonly reported to occur de novo (Ando 2017, Brunet 2021, Frongia 2021, Guillen Sacoto 2020, Sivera 2021, Zech 2020). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.811). Based on available information, this variant is considered to be pathogenic. References: Ando M et al. Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan. Eur J Neurol. 2017 Oct;24(10):1274-1282. PMID: 28771897. Brunet T et al. De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. Clin Genet. 2021 Jul;100(1):14-28. PMID: 33619735. Frongia I et al. Infantile-Onset Charcot-Marie-Tooth Disease With Pyramidal Features and White Matter Abnormalities Due to a De novo MORC2 Gene Variant: A Case Report and Brief Review of the Literature. Front Neurol. 2021 Sep 22;12:718808. PMID: 34630290. Guillen Sacoto MJ et al. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism. Am J Hum Genet. 2020 Aug 6;107(2):352-363. PMID: 32693025. Sivera R et al. Charcot-Marie-Tooth disease due to MORC2 mutations in Spain. Eur J Neurol. 2021 Sep;28(9):3001-3011. PMID: 34189813. Zech M et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol. 2020 Nov;19(11):908-918. PMID: 33098801. -

Inborn genetic diseases Pathogenic:1

Oct 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.995A>G (p.Y332C) alteration is located in exon 14 (coding exon 10) of the MORC2 gene. This alteration results from a A to G substitution at nucleotide position 995, causing the tyrosine (Y) at amino acid position 332 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or observed heterozygous in multiple individuals with features consistent with MORC2-related neurological disorder (Brunet, 2021; Guillen Sacoto, 2020; Frongia, 2021; Ando, 2017; Sivera, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

MORC2-related disorder Pathogenic:1

Feb 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MORC2 c.1181A>G variant is predicted to result in the amino acid substitution p.Tyr394Cys. This variant was reported in individuals with neurodevelopmental disorders or suspected Charcot-Marie-Tooth disease; in several, this variant arose de novo (see, for example, Guillen Sacoto et al. 2020. PubMed ID: 32693025; Zech et al. 2020. PubMed ID: 33098801, supplementary data, reported as p.Tyr332Cys; Sivera et al. 2021. PubMed ID: 34189813; Frongia et al. 2021. PubMed ID: 34630290). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.73		Loss of phosphorylation at Y394 (P = 0.1271);.;
MVP		0.75
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1555938796; hg19: chr22-31334085;