ClinVar Genomic variation as it relates to human health
NM_024339.5(THOC6):c.569G>A (p.Gly190Glu)
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.
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(1); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024339.5(THOC6):c.569G>A (p.Gly190Glu)
Variation ID: 561208 Accession: VCV000561208.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 3076765 (GRCh37) [ NCBI UCSC ] 16: 3026764 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 17, 2018 Nov 20, 2023 Apr 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024339.5:c.569G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077315.2:p.Gly190Glu missense NM_001142350.3:c.569G>A NP_001135822.1:p.Gly190Glu missense NM_001347703.2:c.497G>A NP_001334632.1:p.Gly166Glu missense NM_001347704.2:c.569G>A NP_001334633.1:p.Gly190Glu missense NM_024339.4:c.569G>A NC_000016.10:g.3026764G>A NC_000016.9:g.3076765G>A NG_052595.1:g.7746G>A - Protein change
- G190E, G166E
- Other names
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- Canonical SPDI
- NC_000016.10:3026763:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00013
The Genome Aggregation Database (gnomAD) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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THOC6 | - | - |
GRCh38 GRCh37 |
67 | 109 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Aug 28, 2019 | RCV000680238.12 | |
Pathogenic (4) |
criteria provided, single submitter
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Apr 29, 2023 | RCV001528676.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 17, 2023 | RCV003403573.4 |
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
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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
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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
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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. |
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Uncertain significance
(Jan 01, 2014)
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criteria provided, single submitter
Method: clinical testing
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THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
Affected status: yes
Allele origin:
inherited
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965830.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
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Likely pathogenic
(Oct 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000992693.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
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Likely pathogenic
(Aug 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767178.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
A homozygous missense variant was identified, NM_024339.4(THOC6):c.569G>A in exon 8 of 13 of the THOC6 gene. This substitution is predicted to cause a moderate amino … (more)
A homozygous missense variant was identified, NM_024339.4(THOC6):c.569G>A in exon 8 of 13 of the THOC6 gene. This substitution is predicted to cause a moderate amino acid change from glycine to glutamic acid at position 190 of the protein, NP_077315.2(THOC6):p.(Gly190Glu). The glycine at this position has high conservation (100 vertebrates, UCSC), and is located in the WD4 functional domain. In silico software predicts the missense variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0002% (28 heterozygotes, 0 homozygotes). It has been previously reported in patients with Beaulieu-Boycott-Innes syndrome (ClinVar, Amos, J. et al (2017), Mattioli, F. et al (2019)). In addition, functional studies show that this variant causes abnormal nuclear localisation and decreased THOC1/THOC5 interaction (Mattioli, F. et al (2019)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. (less)
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Pathogenic
(Apr 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001874085.4
First in ClinVar: Sep 19, 2021 Last updated: May 06, 2023 |
Comment:
Published functional studies demonstrate a damaging effect where G190E is detrimental to protein function (Mattioli et al., 2018); In silico analysis supports that this missense … (more)
Published functional studies demonstrate a damaging effect where G190E is detrimental to protein function (Mattioli et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27102954, 30476144, 31421288, 31216405, 34740920, 27535533) (less)
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Likely pathogenic
(Jan 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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THOC6-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119838.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The THOC6 c.569G>A variant is predicted to result in the amino acid substitution p.Gly190Glu. This variant was reported in the compound heterozygous state in at … (more)
The THOC6 c.569G>A variant is predicted to result in the amino acid substitution p.Gly190Glu. This variant was reported in the compound heterozygous state in at least three unrelated individuals with intellectual disability and/or neurodevelopmental phenotypes (Amos et al. 2017. PubMed ID: 27102954; Mattioli et al. 2019. PubMed ID: 30476144; Liu et al. 2019. PubMed ID: 31216405). Functional studies showed that this variant results in abnormal subcellular localization and impaired protein-protein interaction (Mattioli et al. 2019. PubMed ID: 30476144). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3076765-G-A). This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740821.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957718.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975027.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Nov 07, 2020)
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no assertion criteria provided
Method: literature only
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BEAULIEU-BOYCOTT-INNES SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000807692.4
First in ClinVar: Sep 17, 2018 Last updated: Dec 31, 2022 |
Comment on evidence:
For discussion of the c.569G-A transition (c.569G-A, NM_024339.3) in the THOC6 gene, resulting in a gly190-to-glu (G190E) substitution, that was found in compound heterozygous state … (more)
For discussion of the c.569G-A transition (c.569G-A, NM_024339.3) in the THOC6 gene, resulting in a gly190-to-glu (G190E) substitution, that was found in compound heterozygous state in a patient with Beaulieu-Boycott-Innes syndrome (BBIS; 613680) by Amos et al. (2017), see 615403.0004. In a female patient with BBIS, Mattioli et al. (2019) identified compound heterozygosity for mutations in the THOC6 gene: the G190E mutation inherited from her father, and a rare haplotype that included 3 amino acid changes (W100R, V234L, G275D; 615403.0009) inherited from her mother. Both the triple mutant and G190E variants 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) from the 3-variant haplotype 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. (less)
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not provided
(-)
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no classification provided
Method: literature only
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THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001478048.2
First in ClinVar: Jan 26, 2021 Last updated: Oct 01, 2022 |
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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
HelpTitle | Author | Journal | Year | Link |
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Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. | Mattioli F | Human molecular genetics | 2019 | PMID: 30476144 |
Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping. | Amos JS | Clinical genetics | 2017 | PMID: 27102954 |
Text-mined citations for rs199795381 ...
HelpRecord last updated Mar 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.