rs587779380

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_018486.3(HDAC8):c.356C>T(p.Thr119Met) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T119R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

HDAC8
NM_018486.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.47

Publications

4 publications found

Variant links:

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: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Cornelia de Lange syndrome 5
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Wilson-Turner syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

HDAC8 links:

ENSG00000285547 (HGNC:):

ENSG00000285547 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

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-C is described in ClinVar as Pathogenic. ClinVar VariationId is 987749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant X-72567970-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC8	NM_018486.3 link	c.356C>T	p.Thr119Met	missense_variant	Exon 4 of 11	ENST00000373573.9	NP_060956.1	Q9BY41-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9 link	c.356C>T	p.Thr119Met	missense_variant	Exon 4 of 11	1	NM_018486.3	ENSP00000362674.3		Q9BY41-1
ENSG00000285547	ENST00000648922.1 link	c.356C>T	p.Thr119Met	missense_variant	Exon 4 of 12			ENSP00000497072.1		A0A3B3IRV1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 5

Pathogenic:8

Dec 19, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HDAC8 c.356C>T (p.Thr119Met) results in a non-conservative amino acid change located in the Histone deacetylase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182900 control chromosomes (gnomAD). c.356C>T has been reported in the literature in individuals affected with Cornelia de Lange syndrome 5 (Yuan_2015, Salzberg_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories submitted pathogenic classifications for this variant to ClinVar (last evaluated in 2013 and 2014, respectively). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 HDAC8 protein function. ClinVar contains an entry for this variant (Variation ID: 92043). This missense change has been observed in individual(s) with clinical features of Cornelia de Lange syndrome or Say-Barber-Biesecker-Young-Simpson syndrome (PMID: 24375697, 25574841). In at least one individual the variant was observed to be de novo. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 119 of the HDAC8 protein (p.Thr119Met). -

Oct 27, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 20, 2023

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2013

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Nov 19, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

.;.;D;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.3

.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;M;M

PhyloP100

6.5

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.2

.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;N;.;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;T;.;D;D

Sift4G

Pathogenic

0.0

.;.;D;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;.;.;D;D

Polyphen

1.0

.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.72, 0.72, 0.72, 0.83, 0.81, 0.80

MutPred

0.82

Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);.;Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);.;Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);

MVP

0.92

MPC

2.2

ClinPred

1.0

GERP RS

4.9

PromoterAI

-0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over