7-148809370-G-A

Position:

• chr7-148809370-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_004456.5(EZH2):​c.2050C>T​(p.Arg684Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R684H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.83

Genes affected

EZH2 (HGNC:3527): (enhancer of zeste 2 polycomb repressive complex 2 subunit) This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein associates with the embryonic ectoderm development protein, the VAV1 oncoprotein, and the X-linked nuclear protein. This protein may play a role in the hematopoietic and central nervous systems. Multiple alternatively splcied transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Feb 2011]

EZH2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain SET (size 115) in uniprot entity EZH2_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_004456.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-148809369-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EZH2. . Gene score misZ 4.6808 (greater than the threshold 3.09). Trascript score misZ 5.1095 (greater than threshold 3.09). GenCC has associacion of gene with Weaver syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 7-148809370-G-A is Pathogenic according to our data. Variant chr7-148809370-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 158582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148809370-G-A is described in Lovd as [Pathogenic]. Variant chr7-148809370-G-A is described in Lovd as [Pathogenic]. Variant chr7-148809370-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZH2	NM_004456.5	c.2050C>T	p.Arg684Cys	missense_variant	18/20	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.2050C>T	p.Arg684Cys	missense_variant	18/20	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weaver syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 684 of the EZH2 protein (p.Arg684Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Weaver syndrome (PMID: 22190405, 26694085, 29802153). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 158582). 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 EZH2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000158582). A different missense change at the same codon (p.Arg684His) has been reported to be associated with EZH2 related disorder (PMID: 24214728). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Jul 23, 2024	- -

EZH2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2024

The EZH2 c.2050C>T variant is predicted to result in the amino acid substitution p.Arg684Cys. This variant was reported to be causative for Weaver syndrome and has been observed to have arisen de novo in multiple cases (Tatton-Brown et al. 2011. PubMed ID: 22190405; Cohen et al. 2016. PubMed ID: 26694085; Table S1, Zhu et al. 2020. PubMed ID: 33240318). Functional studies showed that this variant impairs the histone methyltransferase activity (Cohen et al. 2016. PubMed ID: 26694085). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2022

Published functional studies demonstrate a damaging effect indicating that R684C impairs histone methyltransferase activity in vitro (Cohen et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26694085, 23568486, 22190405, 24214728, 29276005, 29802153, 33144682, 33240318, 31785789) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;D;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.9	D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.80
MutPred		0.70		.;Loss of sheet (P = 0.0037);.;.;.;.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.7
Varity_R		0.94
gMVP		0.96

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: rs587783626; hg19: chr7-148506462; COSMIC: COSV57449598; COSMIC: COSV57449598;