Submissions for variant NM_001953.5(TYMP):c.1340_1361del (p.Leu447fs)

dbSNP: rs772501604

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825485	SCV000966788	uncertain significance	not specified	2018-03-12	criteria provided, single submitter	clinical testing	The p.Leu452ProfsX60 variant in TYMP has not been previously reported in individ uals with disease, but has been identified in 0.026% (6/22794) of Finnish chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP 772501604). This variant is predicted to remove the last 33 amino acid s of the protein and replace it with a different 60 amino acids. The tail end of the protein is not conserved in mammals, and thus it is unclear what the functi onal effect will be by altering the end of the protein. In summary, the clinical significance of the p.Leu452ProfsX60 variant in TYMP is uncertain. ACMG/AMP Cri teria applied: PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869265	SCV002242708	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the TYMP gene (p.Leu447Profs*?). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the TYMP protein and extend the protein by an uncertain number of additional additional amino acid residues. For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the TYMP protein. Other variant(s) that result in a similarly extended protein product (p.Phe473Serfs*?) have been determined to be pathogenic (PMID: 21412940). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 666945). This frameshift has been observed in individual(s) with clinical features of TYMP-related conditions (Invitae). This variant is present in population databases (rs772501604, gnomAD 0.03%).