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NM_018486.3(HDAC8):c.587T>C (p.Met196Thr) AND Cornelia de Lange syndrome 5

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 16, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003649816.1

Allele description [Variation Report for NM_018486.3(HDAC8):c.587T>C (p.Met196Thr)]

NM_018486.3(HDAC8):c.587T>C (p.Met196Thr)

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.587T>C (p.Met196Thr)
HGVS:
  • NC_000023.11:g.72490970A>G
  • NG_015851.1:g.87134T>C
  • NM_001166418.2:c.314T>C
  • NM_001166419.2:c.587T>C
  • NM_001166448.2:c.278-1929T>C
  • NM_001410725.1:c.587T>C
  • NM_001410727.1:c.551-1929T>C
  • NM_001410728.1:c.314T>C
  • NM_001410729.1:c.587T>C
  • NM_001410730.1:c.551-1929T>C
  • NM_018486.3:c.587T>CMANE SELECT
  • NP_001159890.1:p.Met105Thr
  • NP_001159891.1:p.Met196Thr
  • NP_001397654.1:p.Met196Thr
  • NP_001397657.1:p.Met105Thr
  • NP_001397658.1:p.Met196Thr
  • NP_060956.1:p.Met196Thr
  • NC_000023.10:g.71710820A>G
  • NR_051952.2:n.527T>C
Protein change:
M105T
Molecular consequence:
  • NM_001166448.2:c.278-1929T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001410727.1:c.551-1929T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001410730.1:c.551-1929T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001166418.2:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001166419.2:c.587T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001410725.1:c.587T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001410728.1:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001410729.1:c.587T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_018486.3:c.587T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_051952.2:n.527T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004408110Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Nov 16, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome.

Feng L, Zhou D, Zhang Z, Liu Y, Yang Y.

J Hum Genet. 2014 Sep;59(9):536-9. doi: 10.1038/jhg.2014.60. Epub 2014 Aug 7. Erratum in: J Hum Genet. 2015 Mar;60(3):165.

PubMed [citation]
PMID:
25102094

Exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome.

Feng L, Zhou D, Zhang Z, Liu Y, Yang Y.

J Hum Genet. 2015 Mar;60(3):165. doi: 10.1038/jhg.2014.113. No abstract available.

PubMed [citation]
PMID:
25805374
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004408110.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Met196 amino acid residue in HDAC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25102094, 25805374). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with HDAC8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 196 of the HDAC8 protein (p.Met196Thr).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 28, 2024