NM_018486.3(HDAC8):c.667C>T (p.Arg223Trp) AND Cornelia de Lange syndrome 5

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 20, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000761240.2

Allele description [Variation Report for NM_018486.3(HDAC8):c.667C>T (p.Arg223Trp)]

NM_018486.3(HDAC8):c.667C>T (p.Arg223Trp)

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.667C>T (p.Arg223Trp)

HGVS:

NC_000023.11:g.72489003G>A
NG_015851.1:g.89101C>T
NM_001166418.2:c.394C>T
NM_001166419.2:c.667C>T
NM_001166448.2:c.316C>T
NM_018486.3:c.667C>TMANE SELECT
NP_001159890.1:p.Arg132Trp
NP_001159891.1:p.Arg223Trp
NP_001159920.1:p.Arg106Trp
NP_060956.1:p.Arg223Trp
NC_000023.10:g.71708853G>A
NM_018486.2:c.667C>T
NR_051952.2:n.607C>T

Protein change:

R106W

Links:

dbSNP: rs1556007534

NCBI 1000 Genomes Browser:

rs1556007534

Molecular consequence:

NM_001166418.2:c.394C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166419.2:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166448.2:c.316C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_018486.3:c.667C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_051952.2:n.607C>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
SCV000891196	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25533962, 25741868
SCV004539589	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25533962, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000891196

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 11, 2017)

germline

clinical testing

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

SCV004539589

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 20, 2023)

germline

clinical testing

PubMed (2)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	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

Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study..

Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.

PubMed [citation]

PMID:: 25533962
PMCID:: PMC5955210

See all PubMed Citations (3)

Details of each submission

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000891196.1

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

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

From Invitae, SCV004539589.1

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

Description

ClinVar contains an entry for this variant (Variation ID: 623138). 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. 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. This missense change has been observed in individual(s) with clinical features of Cornelia de Lange syndrome (PMID: 25533962). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 223 of the HDAC8 protein (p.Arg223Trp).

#	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 28, 2024

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