Submissions for variant NM_001953.5(TYMP):c.665A>G (p.Lys222Arg)

gnomAD frequency: 0.00010  dbSNP: rs149977726

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497545	SCV000589523	likely pathogenic	not provided	2016-09-09	criteria provided, single submitter	clinical testing	The K222R variant in the TYMP gene has previously been reported association with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome in an individual who was also heterozygous for frameshift variant in TYMP although the phase of these variants was not determined (Giordano et al., 2008). The K222R variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K222R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species and is predicted to be involved in phosphate binding within the activite site of the thymidine phosphorylase enzyme (Nishino et al., 1999; Pugmire et al., 1998). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497545	SCV002295933	likely pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 222 of the TYMP protein (p.Lys222Arg). This variant is present in population databases (rs149977726, gnomAD 0.03%). This missense change has been observed in individual(s) with mitochondrial neurogastrointestinal encephalopathy (PMID: 9924029). This variant is also known as A2744G. ClinVar contains an entry for this variant (Variation ID: 16656). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYMP protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000018136	SCV003835545	likely pathogenic	Mitochondrial DNA depletion syndrome 1	2024-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000018136	SCV000038415	pathogenic	Mitochondrial DNA depletion syndrome 1	2000-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000018136	SCV000264519	pathogenic	Mitochondrial DNA depletion syndrome 1	2016-01-14	no assertion criteria provided	literature only
Natera, Inc.	RCV001831582	SCV002081624	likely pathogenic	Mitochondrial neurogastrointestinal encephalomyopathy	2021-06-29	no assertion criteria provided	clinical testing