NM_018486.3(HDAC8):c.490C>T (p.Arg164Ter) AND Cornelia de Lange syndrome 5

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 8, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000032915.14

Allele description [Variation Report for NM_018486.3(HDAC8):c.490C>T (p.Arg164Ter)]

NM_018486.3(HDAC8):c.490C>T (p.Arg164Ter)

Gene:

HDAC8:histone deacetylase 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_018486.3(HDAC8):c.490C>T (p.Arg164Ter)

HGVS:

NC_000023.11:g.72495216G>A
NG_015851.1:g.82888C>T
NM_001166418.2:c.217C>T
NM_001166419.2:c.490C>T
NM_001166448.2:c.217C>T
NM_018486.3:c.490C>TMANE SELECT
NP_001159890.1:p.Arg73Ter
NP_001159891.1:p.Arg164Ter
NP_001159920.1:p.Arg73Ter
NP_060956.1:p.Arg164Ter
NC_000023.10:g.71715066G>A
NM_018486.2:c.490C>T
NR_051952.2:n.430C>T

Protein change:

R164*; ARG164TER

Links:

OMIM: 300269.0002; dbSNP: rs397515415

NCBI 1000 Genomes Browser:

rs397515415

Molecular consequence:

NR_051952.2:n.430C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001166418.2:c.217C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001166419.2:c.490C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001166448.2:c.217C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018486.3:c.490C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Cornelia de Lange syndrome 5 (CDLS5)
Identifiers:: MONDO: MONDO:0010471; MedGen: C3550903; Orphanet: 199; OMIM: 300882

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056687	OMIM	no assertion criteria provided	Pathogenic (Sep 13, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000245489	Baylor Genetics - Adult_WES	criteria provided, single submitter (Yang et al. 2013)	Pathogenic (Sep 19, 2014)	de novo	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22885700, 24088041, 26633545
SCV000484415	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (HA_assertions_20161101)	Pathogenic (Nov 10, 2016)	unknown	research	Citation Link,
SCV001445900	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	1	not provided	research
Causasians	de novo	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.

Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, Saitoh K, Komata M, Katou Y, Clark D, Cole KE, De Baere E, Decroos C, Di Donato N, Ernst S, Francey LJ, Gyftodimou Y, Hirashima K, Hullings M, Ishikawa Y, Jaulin C, Kaur M, et al.

Nature. 2012 Sep 13;489(7415):313-7. doi: 10.1038/nature11316.

PubMed [citation]

PMID:: 22885700
PMCID:: PMC3443318

Clinical whole-exome sequencing for the diagnosis of mendelian disorders.

Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, et al.

N Engl J Med. 2013 Oct 17;369(16):1502-11. doi: 10.1056/NEJMoa1306555. Epub 2013 Oct 2.

PubMed [citation]

PMID:: 24088041
PMCID:: PMC4211433

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000056687.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 6-year-old female with features consistent with Cornelia de Lange syndrome (CDLS5; 300882), Deardorff et al. (2012) identified a heterozygous de novo C-to-T transition at nucleotide 490 of the HDAC8 gene resulting in an arg-to-ter codon substitution at codon 164 (R164X). The patient had growth delays, absent speech, and characteristic facial features as well as asymmetric skull, limb length discrepancy, and dysplastic kidneys. This mutation was not seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics - Adult_WES, SCV000245489.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Causasians	1	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (3)

Description

This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 21-year-old female with autism, intellectual disability, hypotonia, hyperextensibility, cardiomyopathy, scoliosis, dysautonomia

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided	(GTR000508680.4)	1	not provided	1	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000484415.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445900.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This nonsense variant found in exon 5 of 11 is predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in patients with Cornelia de Lange syndrome (PMID: 22885700). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.490C>T (p.Arg164Ter) variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2022

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