NM_024339.5(THOC6):c.700G>C (p.Val234Leu) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 22, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000623380.4

Allele description [Variation Report for NM_024339.5(THOC6):c.700G>C (p.Val234Leu)]

NM_024339.5(THOC6):c.700G>C (p.Val234Leu)

Gene:

THOC6:THO complex subunit 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_024339.5(THOC6):c.700G>C (p.Val234Leu)

HGVS:

NC_000016.10:g.3027170G>C
NG_052595.1:g.8152G>C
NM_001142350.3:c.700G>C
NM_001347703.2:c.628G>C
NM_001347704.2:c.700G>C
NM_024339.5:c.700G>CMANE SELECT
NP_001135822.1:p.Val234Leu
NP_001334632.1:p.Val210Leu
NP_001334633.1:p.Val234Leu
NP_077315.2:p.Val234Leu
NC_000016.9:g.3077171G>C
NM_024339.3:c.700G>C
NM_024339.4:c.700G>C

Protein change:

V210L

Links:

OMIM: 615403.0009; dbSNP: rs150940923

NCBI 1000 Genomes Browser:

rs150940923

Molecular consequence:

NM_001142350.3:c.700G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001347703.2:c.628G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001347704.2:c.700G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024339.5:c.700G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000741883	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Feb 22, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31421288, 30476144, 27295358 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000741883

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Feb 22, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.

Gupta N, Yadav S, Gurramkonda VB, Vl R, Sg T, Kabra M.

Eur J Med Genet. 2020 Mar;63(3):103742. doi: 10.1016/j.ejmg.2019.103742. Epub 2019 Aug 14.

PubMed [citation]

PMID:: 31421288

Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability.

Mattioli F, Isidor B, Abdul-Rahman O, Gunter A, Huang L, Kumar R, Beaulieu C, Gecz J, Innes M, Mandel JL, Piton A.

Hum Mol Genet. 2019 Mar 15;28(6):952-960. doi: 10.1093/hmg/ddy391.

PubMed [citation]

PMID:: 30476144

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000741883.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The c.700G>C (p.V234L) alteration is located in coding exon 11 of the THOC6 gene. This alteration results from a G to C substitution at nucleotide position 700, causing the valine (V) at amino acid position 234 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the THOC6 c.700G>C alteration was observed in 0.02% (49/282,608) of total alleles studied, with a frequency of 0.03% (36/129,008) 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.V234 amino acid is conserved in available vertebrate species. The p.V234L amino acid is located in a separate domain than the domains with the p.W100R and p.G275D 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 p.V234L alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

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

Last Updated: Apr 15, 2024

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