X-72567970-G-C

Variant names:

• chrX-72567970-G-C
• rs587779380
• NM_018486.3:c.356C>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_018486.3(HDAC8):​c.356C>G​(p.Thr119Arg) 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. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001448206: By molecular modeling, the amino acid change compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, triggering global structural changes that propagate through the protein scaffold to the catalytic site, creating de facto haploinsufficiency. The effects observed are similar of those described by Decroos and colleagues regarding the p.Gly117Glu replacement, which compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, resulting in a 5% residual enzyme activity.". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T119M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.47
• Publications: 4 publications found

Genes affected

HDAC8 (HGNC:13315): (histone deacetylase 8) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

HDAC8 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Cornelia de Lange syndrome 5

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Wilson-Turner syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285547 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001448206: By molecular modeling, the amino acid change compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, triggering global structural changes that propagate through the protein scaffold to the catalytic site, creating de facto haploinsufficiency. The effects observed are similar of those described by Decroos and colleagues regarding the p.Gly117Glu replacement, which compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, resulting in a 5% residual enzyme activity.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-72567970-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant X-72567970-G-C is Pathogenic according to our data. Variant chrX-72567970-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 987749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018486.3. 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
	HDAC8	NM_018486.3	MANE Select	c.356C>G	p.Thr119Arg	missense	Exon 4 of 11	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.356C>G	p.Thr119Arg	missense	Exon 4 of 12	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410727.1		c.356C>G	p.Thr119Arg	missense	Exon 4 of 10	NP_001397656.1	A6NFW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.356C>G	p.Thr119Arg	missense	Exon 4 of 11	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.356C>G	p.Thr119Arg	missense	Exon 4 of 12	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000412342.6	TSL:1	n.*54C>G		non_coding_transcript_exon	Exon 3 of 7	ENSP00000400180.1	F8WCG4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cornelia de Lange syndrome 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.84		Gain of methylation at T119 (P = 0.0107)
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		1.0
Mutation Taster		=0/100	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: rs587779380; hg19: chrX-71787820;