rs587783626

Variant names:

• chr7-148809370-G-A
• rs587783626
• NM_004456.5:c.2050C>T
• EZH2 p.Arg684Cys

Your query was ambiguous. Multiple possible variants found:

• chr7-148809370-G-A
• chr7-148809370-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001787195: Published functional studies demonstrate a damaging effect indicating that R684C impairs histone methyltransferase activity in vitro (Cohen et al., 2016)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R684L) has been classified as Uncertain significance.

• 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
• Publications: 35 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001787195: Published functional studies demonstrate a damaging effect indicating that R684C impairs histone methyltransferase activity in vitro (Cohen et al., 2016);; SCV005362583: Functional studies showed that this variant impairs the histone methyltransferase activity (Cohen et al. 2016. PubMed ID: 26694085).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004456.5
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 158582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004456.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.2050C>T	p.Arg684Cys	missense	Exon 18 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.2035C>T	p.Arg679Cys	missense	Exon 18 of 20	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.2008C>T	p.Arg670Cys	missense	Exon 18 of 20	NP_001190177.1	Q15910-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.2050C>T	p.Arg684Cys	missense	Exon 18 of 20	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.2035C>T	p.Arg679Cys	missense	Exon 18 of 20	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.1918C>T	p.Arg640Cys	missense	Exon 17 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Weaver syndrome (6)
1	-	-	EZH2-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.7
Varity_R		0.94
gMVP		0.96
Mutation Taster		=4/96	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587783626;

hg19: chr7-148506462;

COSMIC: COSV57449598;

COSMIC: COSV57449598;