Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.27 | TARS | Arina Puzriakova edited their review of gene: TARS: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.26 | TARS | Arina Puzriakova Source NHS GMS was added to TARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 | TARS | Arina Puzriakova Tag watchlist tag was added to gene: TARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 | TARS | Arina Puzriakova Classified gene: TARS as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 | TARS | Arina Puzriakova Added comment: Comment on list classification: Adding this gene as Amber as currently only two unrelated individuals have been reported with variants and trichothiodystrophy (PMID: 31374204). Familial segregation was not reported in either case. Functional studies demonstrate the variants exert a loss-of-function effect but an additional case would help corroborate this gene-disease association (added 'watchlist' tag). At present, CARS1 is the only aminoacyl tRNA synthetase gene for which sufficient evidence has been reported to warrant a Green rating on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.25 | TARS | Arina Puzriakova Gene: tars has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.24 | TARS | Arina Puzriakova Mode of pathogenicity for gene: TARS was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.23 | TARS | Arina Puzriakova Publications for gene: TARS were set to PMID 31374204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.22 | TARS | Arina Puzriakova Phenotypes for gene: TARS were changed from Trichothiodystrophy 7, nonphotosensitive to Trichothiodystrophy 7, nonphotosensitive, OMIM:618546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.21 | TARS | Arina Puzriakova Tag new-gene-name tag was added to gene: TARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 | TARS | Alan Lehmann reviewed gene: TARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 | TARS |
Michael Yau gene: TARS was added gene: TARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Expert list Mode of inheritance for gene: TARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TARS were set to PMID 31374204 Phenotypes for gene: TARS were set to Trichothiodystrophy 7, nonphotosensitive Penetrance for gene: TARS were set to Complete Mode of pathogenicity for gene: TARS was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: TARS was set to GREEN Added comment: Name: threonyl-tRNA synthetase 1; Symbol: TARS1; HGNC ID: 11572 Current Status: Not in R227 Panel. This gene was added to the DDG2P panel in Sept 2019 as a amber gene and the reviwer noted the following: "Non-photosensitive trichothiodystrophy. Disease confidence rating in DDG2P: probable. DDG2P mutation consequence: loss of function. DDG2P allelic requirement: biallelic." Proposed change: GREEN Supporting Evidence: Theil et al (2021) published a multi-centre WES/WGS sequencing study which screened in a group of 24 NPS-TTD individuals with no molecular diagnosis. TTD18PV and TTD5VI are unrelated individuals initially diagnosed with TTD were found to have the following predicted pathogenic variants in the TARS1 gene: TTD18PV: TARS1 c.826A>G p.(Lys276Glu) and TARS1 c.1912C>T p.(Arg638Ter) TTD5VI: Homozygous TARS1 c.680T>C (p.Leu227Pro). Testing of additional individuals with unresolved NPS-TTD by the authors did not identify any further bi-allelic variants suggesting in their cohort of 47, TARS1 variants account for 4% of NPS-TTD cases. In-silico analysis suggest that missense variants result in amino acid substitutions that are close to the core catalytic domain of the protein which may affect its catalytic activity. Quantitative RT-PCR analysis showed only a slight reduction in total TARS mRNA levels in TTD18PV’s primary fibroblasts, while allelic-specific qRT-PCR analysis showed that 90% of the total TARS mRNA molecules are from the missense p.(Lys276Glu) TARS variant with the remaining only 10% from the c.1912C>T variant allele. Immunoblot analysis of whole-cell extracts from both patient’s fibroblasts revealed an approximate 20% reduction in the total cellular amount of full-length TARS. This is consistent with these missense variants causing protein instability. Based on a total of 47 NPS-TTD individuals for bi-allelic TARS1 variants, the authors suggest that TARS1 variants account for 4% of NPS-TTD cases. References: Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Theil AF et al. Am J Hum Genet, 2019 Aug 1. PMID 31374204 Sources: Expert list |