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NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter) AND Dyskeratosis congenita, digenic

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 22, 2022
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV002285189.1

Allele description [Variation Report for NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter)]

NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter)

Genes:
ENOSF1:enolase superfamily member 1 [Gene - OMIM - HGNC]
TYMS:thymidylate synthetase [Gene - OMIM - HGNC]
Variant type:
Insertion
Cytogenetic location:
18p11.32
Genomic location:
Preferred name:
NM_001071.4(TYMS):c.534_535insTG (p.Met179Ter)
HGVS:
  • NC_000018.10:g.669151_669152insTG
  • NG_028255.1:g.16548_16549insTG
  • NM_001071.4:c.534_535insTGMANE SELECT
  • NM_001354867.2:c.455-1541_455-1540insTG
  • NM_001354868.2:c.285_286insTG
  • NP_001062.1:p.Met179Ter
  • NP_001341797.1:p.Met96Ter
  • LRG_783:g.16548_16549insTG
  • NC_000018.9:g.669151_669152insTG
Protein change:
M179*
Links:
OMIM: 188350.0003; dbSNP: rs2144335824
NCBI 1000 Genomes Browser:
rs2144335824
Molecular consequence:
  • NM_001354867.2:c.455-1541_455-1540insTG - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001071.4:c.534_535insTG - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354868.2:c.285_286insTG - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Dyskeratosis congenita, digenic (DKCD)
Identifiers:
MONDO: MONDO:0031057; MedGen: C5774217; OMIM: 620040

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002574904OMIM
no assertion criteria provided
Pathogenic
(Sep 22, 2022) 		germlineliterature only

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

Help

Summary from all submissions

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

Citations

PubMed

Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita.

Tummala H, Walne A, Buccafusca R, Alnajar J, Szabo A, Robinson P, McConkie-Rosell A, Wilson M, Crowley S, Kinsler V, Ewins AM, Madapura PM, Patel M, Pontikos N, Codd V, Vulliamy T, Dokal I.

Am J Hum Genet. 2022 Aug 4;109(8):1472-1483. doi: 10.1016/j.ajhg.2022.06.014. Erratum in: Am J Hum Genet. 2024 Jul 11;111(7):1494. doi: 10.1016/j.ajhg.2024.05.022.

PubMed [citation]
PMID:
35931051
PMCID:
PMC9388389

Details of each submission

From OMIM, SCV002574904.1

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

Description

In 2 sibs (family 4) with digenic dyskeratosis congenita (DKCD; 620040), Tummala et al. (2022) identified a heterozygous 2-bp insertion (c.534_535insTG, NM_001071.4) in the TYMS gene, resulting in a frameshift and premature termination (Met179Ter). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected father. The sibs also carried a common haplotype in the ENOSF1 gene that was inherited from the unaffected mother who did not have the TYMS mutation. This C-A-ins haplotype (rs699517, rs2790, and rs11280056) had been associated with both reduced TYMS and increased ENOSF1 expression. Sequencing also identified a heterozygous variant in intron 1 of the TYMSOS (TYMS opposite strand) gene in both sibs that was inherited from the unaffected mother (MAF of 0.00026 in gnomAD) and may have influenced the phenotype.

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

Last Updated: Dec 24, 2023