NM_152295.5(TARS1):c.1912C>T (p.Arg638Ter) AND Trichothiodystrophy 7, nonphotosensitive

Clinical significance:Pathogenic (Last evaluated: Aug 20, 2019)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000850111.1

Allele description [Variation Report for NM_152295.5(TARS1):c.1912C>T (p.Arg638Ter)]

NM_152295.5(TARS1):c.1912C>T (p.Arg638Ter)

Gene:
TARS1:threonyl-tRNA synthetase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5p13.3
Genomic location:
Preferred name:
NM_152295.5(TARS1):c.1912C>T (p.Arg638Ter)
HGVS:
  • NC_000005.10:g.33466874C>T
  • NM_001258437.1:c.1912C>T
  • NM_001258438.2:c.2011C>T
  • NM_152295.5:c.1912C>TMANE SELECT
  • NP_001245366.1:p.Arg638Ter
  • NP_001245367.1:p.Arg671Ter
  • NP_689508.3:p.Arg638Ter
  • NP_689508.3:p.Arg638Ter
  • NC_000005.9:g.33466979C>T
  • NM_152295.4:c.1912C>T
  • NR_047676.2:n.2155C>T
  • NR_047677.2:n.1873C>T
  • NR_047678.2:n.1843C>T
Protein change:
R638*; ARG638TER
Links:
OMIM: 187790.0001; dbSNP: rs749888012
NCBI 1000 Genomes Browser:
rs749888012
Molecular consequence:
  • NR_047676.2:n.2155C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_047677.2:n.1873C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_047678.2:n.1843C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_001258437.1:c.1912C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258438.2:c.2011C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_152295.5:c.1912C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Trichothiodystrophy 7, nonphotosensitive
Identifiers:
MONDO: MONDO:0032806; MedGen: C5231403; OMIM: 618546

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000992275OMIMno assertion criteria providedPathogenic
(Aug 20, 2019)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype.

Theil AF, Botta E, Raams A, Smith DEC, Mendes MI, Caligiuri G, Giachetti S, Bione S, Carriero R, Liberi G, Zardoni L, Swagemakers SMA, Salomons GS, Sarasin A, Lehmann A, van der Spek PJ, Ogi T, Hoeijmakers JHJ, Vermeulen W, Orioli D.

Am J Hum Genet. 2019 Aug 1;105(2):434-440. doi: 10.1016/j.ajhg.2019.06.017.

PubMed [citation]
PMID:
31374204
PMCID:
PMC6698936

Details of each submission

From OMIM, SCV000992275.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a patient (TTD18PV) with nonphotosensitive trichothiodystrophy (TTD7; 618546), Theil et al. (2019) identified compound heterozygosity for a c.1912C-T transition (c.1912C-T, NM_152295.4) in the TARS gene, resulting in an arg638-to-ter (R638X) substitution within the anticodon-binding domain, and a c.826A-G transition, resulting in a lys276-to-glu (K276E; 187790.0002) substitution at a highly conserved residue. The K276E mutation was not found in public variant databases, whereas the R638X mutation was present in the ExAC database, only in heterozygosity, at an allele frequency of 0.00008661. Familial segregation was not reported. Immunoblot analysis of patient fibroblast lysates revealed an approximately 80% reduction in full-length TARS compared to control fibroblasts. Allele-specific qRT-PCR showed that only 10% of total TARS mRNA in TTD18PV fibroblasts originated from R638X, suggesting that most TARS proteins contained the K276E variant, consistent with severe protein instability of the missense mutation. Plasmid-shuffling experiments in a yeast knockout strain deprived of the TARS ortholog Ths1 demonstrated dramatically reduced growth with either mutant compared to wildtype TARS. Analysis of steady-state aminoacylation reactions on protein lysates from patient fibroblasts showed an approximately 70 to 80% reduction of threonine tRNA charging activity compared to control fibroblasts, confirming a loss-of-function effect of the mutations.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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