VCV000983559.2 - ClinVar

NM_024339.5(THOC6):c.[298T>A;700G>C824G>A]

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.

(2)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This haplotype includes the following variants

NM_024339.5(THOC6):c.[298T>A;700G>C824G>A]

Other names: THOC6, HAPLOTYPE, THR100ARG, VAL234LEU, GLY275ASP
HAPLOTYPE, THR100ARG, VAL234LEU, GLY275ASP
Functional consequence: -
Links: OMIM: 615403.0009

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.
THOC6		-	-	GRCh38 GRCh37	86	130

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.
THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome	Pathogenic (2)	no assertion criteria provided	Nov 6, 2020	RCV001263559.4

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 06, 2020)	no assertion criteria provided Method: literature only	BEAULIEU-BOYCOTT-INNES SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV001441623.1 First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020	Publications: PubMed (1) PubMed: 30476144 Comment on evidence: In a boy with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), Mattioli et al. (2019) identified homozygosity for a rare haplotype including 3 amino acid changes (W100R, V234L, … (more) In a boy with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), Mattioli et al. (2019) identified homozygosity for a rare haplotype including 3 amino acid changes (W100R, V234L, G275D) in the THOC6 gene due to maternal uniparental disomy of chromosome 16. The mutation was found by trio exome sequencing. The triple mutant changed the physiologic localization of the THOC6 protein from its normal nuclear location to an abnormal cytosolic localization as well as its interaction with 2 THO subunits, THOC1 (606930) and THOC5 (612733). Two of the amino acid changes (W100R and G275D) were predicted on their own to be deleterious according to most programs used, possibly resulting in pathogenicity of the haplotype. The W100R variant was predicted to be most pathogenic because it alters a tryptophan located in a WD-repeat domain, which is usually implicated in multiprotein assembly and interaction. The W100R variant was the only one of the 3 in the haplotype that on its own affected the nuclear localization of THOC6. Another patient reported by Mattioli et al. (2019) was compound heterozygous for the 3-amino acid haplotype and a missense mutation (G190E; 615403.0005). (less)
Pathogenic (Aug 05, 2020)	no assertion criteria provided Method: literature only	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001478046.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (4) PubMed: 32790266‚ 27295358‚ 30476144‚ 31421288 BookShelf: NBK560442 BookShelf: NBK560442 Comment: The 3 missense variants reported as a common haplotype

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Implementation of Exome Sequencing in Prenatal Diagnostics: Chances and Challenges.	Janicki E	Diagnostics (Basel, Switzerland)	2023	PMID: 36900003
Implementation of Exome Sequencing in Prenatal Diagnostics: Chances and Challenges.	Janicki E	Diagnostics (Basel, Switzerland)	2023	PMID: 36900003
Implementation of Exome Sequencing in Prenatal Diagnostics: Chances and Challenges.	Janicki E	Diagnostics (Basel, Switzerland)	2023	PMID: 36900003
Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature.	Ruaud L	Birth defects research	2022	PMID: 35426486
Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature.	Ruaud L	Birth defects research	2022	PMID: 35426486
Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature.	Ruaud L	Birth defects research	2022	PMID: 35426486
First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.	Gupta N	European journal of medical genetics	2020	PMID: 31421288
First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.	Gupta N	European journal of medical genetics	2020	PMID: 31421288
First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.	Gupta N	European journal of medical genetics	2020	PMID: 31421288
First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.	Gupta N	European journal of medical genetics	2020	PMID: 31421288
Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability.	Mattioli F	Human molecular genetics	2019	PMID: 30476144
Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability.	Mattioli F	Human molecular genetics	2019	PMID: 30476144
Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability.	Mattioli F	Human molecular genetics	2019	PMID: 30476144
Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability.	Mattioli F	Human molecular genetics	2019	PMID: 30476144
Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.	Casey J	Clinical dysmorphology	2016	PMID: 27295358
Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.	Casey J	Clinical dysmorphology	2016	PMID: 27295358
Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.	Casey J	Clinical dysmorphology	2016	PMID: 27295358
Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.	Casey J	Clinical dysmorphology	2016	PMID: 27295358
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Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_024339.5(THOC6):c.[298T>A;700G>C824G>A]

Variant Details

NM_024339.5(THOC6):c.[298T>A;700G>C824G>A]

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...