chr7-148811696-C-T

Variant names:

• chr7-148811696-C-T
• rs587783625
• NM_004456.5:c.1876G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_004456.5(EZH2):​c.1876G>A​(p.Val626Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.62
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Weaver syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a domain SET (size 115) in uniprot entity EZH2_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_004456.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 7-148811696-C-T is Pathogenic according to our data. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in CliVar as Pathogenic. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.1876G>A	p.Val626Met	missense_variant	Exon 16 of 20	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.1876G>A	p.Val626Met	missense_variant	Exon 16 of 20	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726748

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weaver syndrome Pathogenic:4

Jul 30, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This is a de novo variant in EZH2. The patient's phenotype fits perfectly with Weaver Syndrome with tall stature and advanced bone age. This same variant is already in ClinVar in another patient with Weaver Syndrome. -

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 626 of the EZH2 protein (p.Val626Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Weaver Syndrome (PMID: 29244146). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 158579). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EZH2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EZH2 function (PMID: 29244146). For these reasons, this variant has been classified as Pathogenic. -

EZH2-related disorder Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 12-04-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.4	.;M;.;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	N;D;D;N;N;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.93
MutPred		0.56		.;Loss of catalytic residue at V621 (P = 0.1444);.;.;.;.;
MVP		0.98
MPC		2.5
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.88
gMVP		0.72
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783625; hg19: chr7-148508788; COSMIC: COSV57451459;