ClinVar Genomic variation as it relates to human health
NM_024339.5(THOC6):c.824G>A (p.Gly275Asp)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024339.5(THOC6):c.824G>A (p.Gly275Asp)
Variation ID: 521349 Accession: VCV000521349.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 3027379 (GRCh38) [ NCBI UCSC ] 16: 3077380 (GRCh37) [ 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 Apr 15, 2018 Aug 4, 2024 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024339.5:c.824G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077315.2:p.Gly275Asp missense NM_001142350.3:c.810+99G>A intron variant NM_001347703.2:c.752G>A NP_001334632.1:p.Gly251Asp missense NM_001347704.2:c.824G>A NP_001334633.1:p.Gly275Asp missense NM_024339.4:c.824G>A NC_000016.10:g.3027379G>A NC_000016.9:g.3077380G>A NG_052595.1:g.8361G>A - Protein change
- G275D, G251D
- Other names
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- Canonical SPDI
- NC_000016.10:3027378: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
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 | ||
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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
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. |
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THOC6 | - | - |
GRCh38 GRCh37 |
84 | 128 |
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
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. |
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Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2021 | RCV000624518.5 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV000850494.15 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2021 | RCV001541157.20 |
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
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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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Pathogenic
(Feb 02, 2019)
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criteria provided, single submitter
Method: research
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Beaulieu-Boycott-Innes syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Medgenome Labs Pvt Ltd
Accession: SCV000920768.1
First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019
Comment:
The haplotype c. [298T>A; 700G>C; 824G>A] in the parents were heterozygous.
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Number of individuals with the variant: 4
Clinical Features:
Global developmental delay (present) , Abnormal facial shape (present) , Synophrys (present) , Deeply set eye (present) , Short palpebral fissure (present) , Epicanthus (present) … (more)
Global developmental delay (present) , Abnormal facial shape (present) , Synophrys (present) , Deeply set eye (present) , Short palpebral fissure (present) , Epicanthus (present) , Plagiocephaly (present) , Cryptorchidism (present) , Congenital elevation of scapula (present) , Failure to thrive (present) (less)
Family history: yes
Ethnicity/Population group: South Asian
Geographic origin: India
Secondary finding: no
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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: SCV000992694.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
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Likely pathogenic
(Nov 09, 2020)
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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: SCV001759117.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
Functional studies of the p.[W100R; G275D; V234L] haplotype suggest a damaging effect with abnormal nuclear localization and decreased interaction with protein partners from the THO … (more)
Functional studies of the p.[W100R; G275D; V234L] haplotype suggest a damaging effect with abnormal nuclear localization and decreased interaction with protein partners from the THO complex, and the G275D variant on its own was also suggested to decrease interaction with protein partners (Mattioli et al., 2019); 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: 31216405, 31421288, 30476144, 27295358, 26739162, 20503307, 23621916, 27102954, 15998806, 19059247, 11060033) (less)
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Pathogenic
(Feb 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741884.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.824G>A (p.G275D) alteration is located in coding exon 12 of the THOC6 gene. This alteration results from a G to A substitution at nucleotide … (more)
The c.824G>A (p.G275D) alteration is located in coding exon 12 of the THOC6 gene. This alteration results from a G to A substitution at nucleotide position 824, causing the glycine (G) at amino acid position 275 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD) database, the THOC6 c.824G>A alteration was observed in 0.02% (49/281,212) of total alleles studied, with a frequency of 0.03% (36/128,392) in the European (non-Finnish) subpopulation. The c.298T>A (p.W100R), c.700G>C (p.V234L), and c.824G>A (p.G275D) alterations make up a known haplotype which was previously reported homozygous or compound heterozygous with another alteration in THOC1 in multiple patients with Beaulieu–Boycott–Innes syndrome (Casey, 2016; Mattioli, 2019; Gupta, 2020). The patients were reported to have intellectual disability, varying dysmorphic features, and other congenital anomalies including cardiac, genitourinary, renal, and skeletal malformations. The p.G275 amino acid is conserved in available vertebrate species. The p.G275D amino acid is located in a separate domain than the domains with the p.W100R and p.V234L amino acids and together may affect the functionality of the larger WD40 domain. Functional expression assays demonstrated that the c.(298T>A; 700G>C; 824G>C) haplotype in THOC6 alters THOC6 physiological nuclear localization and its interaction with other members of the THO complex, THOC1 and THOC5 and that the pathogenicity of the haplotype results from a combined effect of at least two of the three missense changes (Mattioli, 2019). The in silico prediction for the p.G275D alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
Affected status: yes
Allele origin:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053901.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Oct 21, 2022)
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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: yes
Allele origin:
inherited
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045873.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Proportionate short stature (present) , Microcephaly (present) , Global developmental delay (present) , Fetal growth restriction (present)
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Pathogenic
(Feb 14, 2023)
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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: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175811.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense c.824G>A(p.Gly275Asp) variant in THOC6 has been reported in homozygous state in multiple individuals affected with Beaulieu–Boycott–Innes syndrome (Mattioli F, et. al., 2019; Gupta … (more)
The missense c.824G>A(p.Gly275Asp) variant in THOC6 has been reported in homozygous state in multiple individuals affected with Beaulieu–Boycott–Innes syndrome (Mattioli F, et. al., 2019; Gupta N, et. al., 2020). Functional studies show that this variant causes abnormal protein localization (Mattioli F, et. al., 2019). The variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic (multiple submission). The amino acid change p.Gly275Asp in THOC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 275 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jul 17, 2023)
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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: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768719.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Beaulieu-Boycott-Innes syndrome (MIM#613680). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (49 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated WD6 repeat (PMID: 30476144). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as likely pathogenic, a VUS and pathogenic (ClinVar, LOVD, Decipher). It has also been reported as part of a haplotype in multiple homozygous or compound heterozygous individuals with intellectual disability (PMID: 30476144, 31421288, 27295358, 35426486, 36900003). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes impaired THOC1/5 interactions (PMID: 30476144). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Nov 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002063479.18
First in ClinVar: Jan 29, 2022 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 2
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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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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 |
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 |
Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies. | Casey J | Clinical dysmorphology | 2016 | PMID: 27295358 |
Text-mined citations for rs200426926 ...
HelpRecord last updated Aug 04, 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.