rs397515548

chr7-148807669-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM5 PP2 PP5_Very_Strong

The NM_004456.5(EZH2):c.2233G>A(p.Glu745Lys) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E745D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004456.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-148807667-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 975993.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, EZH2
• PP5: Variant 7-148807669-C-T is Pathogenic according to our data. Variant chr7-148807669-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148807669-C-T is described in Lovd as [Pathogenic]. Variant chr7-148807669-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.2233G>A	p.Glu745Lys	missense_variant	20/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.2233G>A	p.Glu745Lys	missense_variant	20/20	1	NM_004456.5	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445944 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 717420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weaver syndrome Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 12, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 745 of the EZH2 protein (p.Glu745Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Weaver syndrome (PMID: 22190405, 23239504, 24214728, 29620724). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65675). 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 95%. Experimental studies have shown that this missense change affects EZH2 function (PMID: 26694085). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

EZH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2023

The EZH2 c.2233G>A variant is predicted to result in the amino acid substitution p.Glu745Lys. This variant has been reported in three individuals with EZH2-related phenotpes; in two of the subjects, this variant was found to be de novo (Tatton-Brown et al 2011. PubMed ID: 22190405; Al-Salem A et al 2012. PubMed ID: 23239504; Maddirevula S et al 2018. PubMed ID: 29620724, Table S6). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;D
Polyphen		0.75	P;B;P;B;P;P
Vest4		0.96
MutPred		0.47		.;Gain of ubiquitination at E740 (P = 0.009);.;.;.;.;
MVP		1.0
MPC		1.7
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397515548; hg19: chr7-148504761; COSMIC: COSV57447594; COSMIC: COSV57447594;