NM_018486.3(HDAC8):c.356C>T (p.Thr119Met) AND Cornelia de Lange syndrome 5

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: May 4, 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:: RCV000077779.11

Allele description

NM_018486.3(HDAC8):c.356C>T (p.Thr119Met)

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.356C>T (p.Thr119Met)

HGVS:

NC_000023.11:g.72567970G>A
NG_015851.1:g.10134C>T
NM_001166418.2:c.164+4087C>T
NM_001166419.2:c.356C>T
NM_001166420.2:c.356C>T
NM_001166422.2:c.356C>T
NM_001166448.2:c.164+4087C>T
NM_018486.3:c.356C>TMANE SELECT
NP_001159891.1:p.Thr119Met
NP_001159892.1:p.Thr119Met
NP_001159894.1:p.Thr119Met
NP_060956.1:p.Thr119Met
NC_000023.10:g.71787820G>A
NM_001166419.1:c.356C>T
NM_018486.2:c.356C>T

Protein change:

T119M

Links:

dbSNP: rs587779380

NCBI 1000 Genomes Browser:

rs587779380

Molecular consequence:

NM_001166418.2:c.164+4087C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001166448.2:c.164+4087C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001166419.2:c.356C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166420.2:c.356C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166422.2:c.356C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_018486.3:c.356C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000109590	McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University	no assertion criteria provided	Pathogenic (Dec 18, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000195848	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	no assertion criteria provided	Pathogenic (Dec 2, 2014)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV001362109	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 19, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24375697, 30158690, 25574841 Citation Link,
SCV001407645	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 6, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24375697, 25574841, 28492532
SCV001521187	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 19, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059697	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 27, 2021)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002516538	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

Yuan B, Neira J, Pehlivan D, Santiago-Sim T, Song X, Rosenfeld J, Posey JE, Patel V, Jin W, Adam MP, Baple EL, Dean J, Fong CT, Hickey SE, Hudgins L, Leon E, Madan-Khetarpal S, Rawlins L, Rustad CF, Stray-Pedersen A, Tveten K, Wenger O, et al.

Genet Med. 2019 Mar;21(3):663-675. doi: 10.1038/s41436-018-0085-6. Epub 2018 Aug 30.

PubMed [citation]

PMID:: 30158690
PMCID:: PMC6395558

DIAMUND: direct comparison of genomes to detect mutations.

Salzberg SL, Pertea M, Fahrner JA, Sobreira N.

Hum Mutat. 2014 Mar;35(3):283-8. doi: 10.1002/humu.22503.

PubMed [citation]

PMID:: 24375697
PMCID:: PMC4031744

See all PubMed Citations (5)

Details of each submission

From McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, SCV000109590.1

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

#	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

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000195848.2

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

#	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		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362109.1

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

Description

Variant summary: HDAC8 c.356C>T (p.Thr119Met) results in a non-conservative amino acid change located in the Histone deacetylase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182900 control chromosomes (gnomAD). c.356C>T has been reported in the literature in individuals affected with Cornelia de Lange syndrome 5 (Yuan_2015, Salzberg_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories submitted pathogenic classifications for this variant to ClinVar (last evaluated in 2013 and 2014, respectively). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From Invitae, SCV001407645.5

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 119 of the HDAC8 protein (p.Thr119Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cornelia de Lange syndrome or Say-Barber-Biesecker-Young-Simpson syndrome (PMID: 24375697, 25574841). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 92043). 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 expected to disrupt HDAC8 protein function. For these reasons, this variant has been classified as Pathogenic.

#	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

From Baylor Genetics, SCV001521187.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	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		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV002059697.1

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

#	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		not provided	not provided	not provided	not provided

From Mendelics, SCV002516538.1

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

#	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: Feb 14, 2024

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