NM_018486.3(HDAC8):c.932C>T (p.Thr311Met) AND Cornelia de Lange syndrome 5

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 8, 2022
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:: RCV000032917.20

Allele description [Variation Report for NM_018486.3(HDAC8):c.932C>T (p.Thr311Met)]

NM_018486.3(HDAC8):c.932C>T (p.Thr311Met)

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.932C>T (p.Thr311Met)

HGVS:

NC_000023.11:g.72462077G>A
NG_015851.1:g.116027C>T
NM_001166418.2:c.659C>T
NM_018486.3:c.932C>TMANE SELECT
NP_001159890.1:p.Thr220Met
NP_060956.1:p.Thr311Met
NC_000023.10:g.71681927G>A
NM_018486.2:c.932C>T
NR_051952.2:n.872C>T
Q9BY41:p.Thr311Met
c.932C>T(p.T311M)

Protein change:

T220M; THR311MET

Links:

UniProtKB: Q9BY41#VAR_069141; OMIM: 300269.0004; dbSNP: rs397515417

NCBI 1000 Genomes Browser:

rs397515417

Molecular consequence:

NM_001166418.2:c.659C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_018486.3:c.932C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_051952.2:n.872C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000056689	OMIM	no assertion criteria provided	Pathogenic (Sep 13, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000747092	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2018)	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 30158690
SCV004300114	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 8, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22885700, 30158690, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000056689

OMIM

no assertion criteria provided

Pathogenic
(Sep 13, 2012)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000747092

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 8, 2018)

de novo

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004300114

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 8, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000056689.1

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

Description

In a 1-year-old female with severe growth and cognitive delays and facial features of classic Cornelia de Lange syndrome (CDLS5; 300882), Deardorff et al. (2012) identified a de novo C-to-T transition at nucleotide 932 in the HDAC8 gene, resulting in a thr-to-met substitution at codon 311 (T311M). The infant also had large fontanels, pulmonary stenosis, and unilateral hearing loss. She had no limb anomalies. 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, SCV000747092.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (2)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004300114.1

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

Description

Experimental studies have shown that this missense change affects HDAC8 function (PMID: 22885700). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 not expected to disrupt HDAC8 protein function. ClinVar contains an entry for this variant (Variation ID: 39712). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 22885700, 30158690). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 311 of the HDAC8 protein (p.Thr311Met).

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

Last Updated: Sep 29, 2024

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