ClinVar Miner

Submissions for variant NM_001953.5(TYMP):c.433G>A (p.Gly145Arg)

gnomAD frequency: 0.00007  dbSNP: rs121913037
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001049989 SCV001214074 pathogenic not provided 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 145 of the TYMP protein (p.Gly145Arg). This variant is present in population databases (rs121913037, gnomAD 0.007%). This missense change has been observed in individuals with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (PMID: 9924029, 10852545, 16995425). It has also been observed to segregate with disease in related individuals. This variant is also known as G1419A. ClinVar contains an entry for this variant (Variation ID: 16655). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000018135 SCV002021572 likely pathogenic Mitochondrial DNA depletion syndrome 1 2021-02-03 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000018135 SCV002578931 likely pathogenic Mitochondrial DNA depletion syndrome 1 2022-03-29 criteria provided, single submitter clinical testing
GeneDx RCV001049989 SCV002757027 likely pathogenic not provided 2022-11-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 19748572, 25525159, 9924029, 21820356, 16995425, 20301358, 18787099, 34288589)
Fulgent Genetics, Fulgent Genetics RCV000018135 SCV002811634 likely pathogenic Mitochondrial DNA depletion syndrome 1 2021-12-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000018135 SCV004029355 pathogenic Mitochondrial DNA depletion syndrome 1 2023-07-25 criteria provided, single submitter clinical testing Variant summary: TYMP c.433G>A (p.Gly145Arg) results in a non-conservative amino acid change located in the Glycosyl transferase, family 3 (IPR000312) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250760 control chromosomes. c.433G>A has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (Example: Nishino_1999, Zaidman_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9924029, 33533561). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000018135 SCV004207500 pathogenic Mitochondrial DNA depletion syndrome 1 2023-10-30 criteria provided, single submitter clinical testing
OMIM RCV000018135 SCV000038414 pathogenic Mitochondrial DNA depletion syndrome 1 1999-01-29 no assertion criteria provided literature only
GeneReviews RCV000018135 SCV000264509 pathogenic Mitochondrial DNA depletion syndrome 1 2016-01-14 no assertion criteria provided literature only
Natera, Inc. RCV001276278 SCV001462372 likely pathogenic Mitochondrial neurogastrointestinal encephalomyopathy 2020-09-16 no assertion criteria provided clinical testing

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