VCV000092043.10 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 92043 Accession: VCV000092043.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 72567970 (GRCh38) [ NCBI UCSC ] X: 71787820 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 8, 2014	Feb 14, 2024	May 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_018486.3:c.356C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060956.1:p.Thr119Met	missense
NM_001166418.2:c.164+4087C>T		intron variant
NM_001166419.2:c.356C>T	NP_001159891.1:p.Thr119Met	missense
NM_001166420.2:c.356C>T	NP_001159892.1:p.Thr119Met	missense
NM_001166422.2:c.356C>T	NP_001159894.1:p.Thr119Met	missense
NM_001166448.2:c.164+4087C>T		intron variant
NC_000023.11:g.72567970G>A
NC_000023.10:g.71787820G>A
NG_015851.1:g.10134C>T

... more HGVS ... less HGVS

Protein change

T119M

Other names

Canonical SPDI

NC_000023.11:72567969:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA331778 dbSNP: rs587779380 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HDAC8		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	318	453

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cornelia de Lange syndrome 5	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000077779.12

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cornelia de Lange syndrome 5 Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001521187.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Oct 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cornelia de Lange syndrome 5 Affected status: yes Allele origin: de novo	Centogene AG - the Rare Disease Company Accession: SCV002059697.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Cornelia de Lange syndrome 5 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516538.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Dec 19, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cornelia de Lange syndrome 5 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362109.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (3) PubMed: 24375697‚ 30158690‚ 25574841 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cornelia de Lange syndrome 5 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001407645.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24375697‚ 25574841 Comment: 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). … (more) 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. (less)
Pathogenic (Dec 02, 2014)	no assertion criteria provided Method: research	Cornelia de Lange Syndrome 5 (CdLS5) Affected status: yes Allele origin: de novo	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000195848.2 First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015	Publications: PubMed (1) PubMed: 25574841
Pathogenic (Dec 18, 2013)	no assertion criteria provided Method: clinical testing	Cornelia de Lange syndrome 5 Affected status: yes Allele origin: germline	McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University Accession: SCV000109590.1 First in ClinVar: Jan 08, 2014 Last updated: Jan 08, 2014	Publications: PubMed (1) PubMed: 24375697

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.	Yuan B	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30158690
Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.	Yuan B	The Journal of clinical investigation	2015	PMID: 25574841
DIAMUND: direct comparison of genomes to detect mutations.	Salzberg SL	Human mutation	2014	PMID: 24375697

Text-mined citations for rs587779380 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587779380 ...