rs398122909

chrX-72462051-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_018486.3(HDAC8):c.958G>A(p.Gly320Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.48

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_018486.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant X-72462051-C-T is Pathogenic according to our data. Variant chrX-72462051-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39713.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=1}. Variant chrX-72462051-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-72462051-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.958G>A	p.Gly320Arg	missense_variant	9/11	ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.958G>A	p.Gly320Arg	missense_variant	9/11	1	NM_018486.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2022	This missense change has been observed in individual(s) with Cornelia de Lange syndrome or intellectual disability (PMID: 22885700, 24403048, 26671848, 27159028). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HDAC8 function (PMID: 22885700, 24403048, 26725122). 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 not expected to disrupt HDAC8 protein function. ClinVar contains an entry for this variant (Variation ID: 39713). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 320 of the HDAC8 protein (p.Gly320Arg). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2017

The p.G320R variant (also known as c.958G>A), located in coding exon 9 of the HDAC8 gene, results from a G to A substitution at nucleotide position 958. The glycine at codon 320 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified to occur de novo in two males with clinical features consistent with a diagnosis of Cornelia de Lange syndrome (CdLS); however, paternity was not confirmed (Deardorff MA et al. Nature, 2012 Sep;489:313-7; Parenti I et al. Clin. Genet., 2016 May;89:564-73). Functional studies in lymphoblastoid cell lines (LCLs) from a hemizygous male with the p.G320R variant demonstrated that this alteration results in minimal protein expression and decreased deacetylase activity (Deardorff MA et al. Nature, 2012 Sep;489:313-7; Kaiser FJ et al. Hum. Mol. Genet., 2014 Jun;23:2888-900). This alteration was also reported as de novo in a female with synophrys, micrognathia, growth delay, postnatal low weight and height, hypotonia, seizures, moderate intellectual disability with language delay, and autistic traits. Extreme X-chromosome inactivation was observed with only the wild-type allele being expressed in blood, however this may not be representative of other tissues, such as the brain (Fieremans N et al. Hum. Mutat., 2016 Aug;37:804-11). This amino acid position is highly conserved in mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2021

Published functional studies demonstrate a damaging effect on enzyme activity (Kaiser FJ, 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32564284, 27535533, 26671848, 22885700, 30293248, 27159028, 24403048) -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Human Genetics Laboratory, State University of Rio de Janeiro

Oct 07, 2019

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

literature only

Center for Human Genetics, University of Leuven

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.086	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.90, 0.82
MutPred		0.68		Gain of MoRF binding (P = 0.0291);.;Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);.;.;.;Gain of MoRF binding (P = 0.0291);.;Gain of MoRF binding (P = 0.0291);.;.;Gain of MoRF binding (P = 0.0291);.;Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);.;
MVP		0.92
MPC		2.3
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs398122909; hg19: chrX-71681901;