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

gnomAD frequency: 0.00020  dbSNP: rs150940923

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623380	SCV000741883	pathogenic	Inborn genetic diseases	2021-02-22	criteria provided, single submitter	clinical testing	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.
Medgenome Labs Pvt Ltd	RCV000850496	SCV000920767	uncertain significance	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome	2019-02-02	criteria provided, single submitter	research
Baylor Genetics	RCV000850496	SCV000992696	uncertain significance	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome		criteria provided, single submitter	clinical testing
GeneDx	RCV001553458	SCV001774329	uncertain significance	not provided	2020-11-13	criteria provided, single submitter	clinical testing	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, however, the V234L variant on its own did not affect nuclear localization nor interaction with protein partners (Mattioli et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33144682, 31216405, 31421288, 30476144, 27295358, 26739162, 20503307, 23621916, 27102954, 15998806, 19059247, 11060033)
CeGaT Center for Human Genetics Tuebingen	RCV001553458	SCV002063478	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000850496	SCV002768513	likely benign	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. 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 valine to leucine. (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 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated WD5 repeat (PMID: 30476144). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has some previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as likely pathogenic, likely benign and as a VUS (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) 1010 - Functional evidence for this variant is inconclusive. Functional studies of this variant alone showed normal protein localization and THOC1/5 interactions (PMID: 30476144). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000850496	SCV004045872	pathogenic	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome	2022-10-21	criteria provided, single submitter	clinical testing