rs1064797002

chr2-239144705-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_001378414.1(HDAC4):c.743C>T(p.Pro248Leu) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P248A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HDAC4 NM_001378414.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 9.01

Genes affected

HDAC4 (HGNC:14063): (histone deacetylase 4) 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 II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-239144706-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1344563.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, HDAC4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 2-239144705-G-A is Pathogenic according to our data. Variant chr2-239144705-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424498.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC4	NM_001378414.1	c.743C>T	p.Pro248Leu	missense_variant	8/27	ENST00000543185.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC4	ENST00000543185.6	c.743C>T	p.Pro248Leu	missense_variant	8/27	5	NM_001378414.1	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with central hypotonia and dysmorphic facies Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A - VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a proline to a leucine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0704 – A comparable variant (p.Pro248Ala) has low previous evidence for pathogenicity in a single patient with intellectual disability and joint laxity (Decipher). (P) 0802 - Moderate previous evidence of pathogenicity in three unrelated individuals with intellectual disability and joint laxity (Decipher, ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2023

The c.743C>T (p.P248L) alteration is located in exon 8 (coding exon 7) of the HDAC4 gene. This alteration results from a C to T substitution at nucleotide position 743, causing the proline (P) at amino acid position 248 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant and another alteration at the same codon, c.742C>G (p.P248A), have been determined to be the result of a de novo mutation in multiple individuals with features consistent with HDAC4-related neurodevelopmental disorder (Wakeling, 2021). This amino acid position is highly conserved in available vertebrate species. The p.P248L amino acid is located within the nuclear localization domain and is an important residue for protein binding and HDAC4 export from the nucleus. The location of this alteration is 2 amino acids away from a phosphorylated serine (p.S246), the phosphorylation of which is required for export of HDAC4 from the nucleus (Wang, 2001). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2018

The P248L variant in the HDAC4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P248L variant is not observed in large population cohorts (Lek et al., 2016). The P248L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P248L as a pathogenic variant. -

Chromosome 2q37 deletion syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Dec 21, 2021

PS2, PM1, PM2, PP3, PP5 -

Intellectual disability, profound Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Elsea Laboratory, Baylor College of Medicine

Aug 03, 2020

- -

Brachydactyly syndrome type E Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Multiple laboratories identified the variant in this registry participant. Variant interpreted as Pathogenic and reported, most recently, on 03-29-2019 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	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.9	D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.33		Loss of glycosylation at P248 (P = 0.0323);.;
MVP		0.87
MPC		1.0
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064797002; hg19: chr2-240066401; COSMIC: COSV61866558; COSMIC: COSV61866558;