Submissions for variant NM_001953.5(TYMP):c.1160-1G>A

gnomAD frequency: 0.00004  dbSNP: rs797044455

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606736	SCV000731948	pathogenic	Mitochondrial neurogastrointestinal encephalomyopathy	2017-08-29	criteria provided, single submitter	clinical testing	The c.1160-1G>A (NM_001953.4) variant in TYMP has been reported in 4 homozygous and 1 compound heterozygous individuals with mitochondrial neurogastrointestinal encephalopathy disease (MNGIE) (Nishino 2000 and Kocaefe 2003). This variant ha s also been identified in 1/14978 of European chromosomes by Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org), though this frequency is lo w enough to be consistent with a recessive carrier frequency. This variant occur s in the invariant region (+/- 1,2) of the splice consensus sequence and is pred icted to cause altered splicing leading to an abnormal or absent protein. Bialle lic loss of function in the TYMP gene is associated with MNGIE. In summary, this variant meets our criteria to be classified as pathogenic for MNGIE in an autos omal recessive manner based on its biallelic occurrence in affected individuals and predicted impact on the protein.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000208629	SCV001367782	pathogenic	Mitochondrial DNA depletion syndrome 1	2019-05-07	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3.
Department of Pathophysiology and Transplantation, University of Milan	RCV000208629	SCV001438019	pathogenic	Mitochondrial DNA depletion syndrome 1	2020-07-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001255087	SCV001500762	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001255087	SCV001578027	pathogenic	not provided	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the TYMP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TYMP are known to be pathogenic (PMID: 9924029, 15781193). This variant is present in population databases (no rsID available, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 10852545, 12529715). This variant is also known as G3867C, G5314A. ClinVar contains an entry for this variant (Variation ID: 223064). 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.
Baylor Genetics	RCV000208629	SCV004207505	pathogenic	Mitochondrial DNA depletion syndrome 1	2024-03-21	criteria provided, single submitter	clinical testing
GeneReviews	RCV000208629	SCV000264546	pathogenic	Mitochondrial DNA depletion syndrome 1	2016-01-14	no assertion criteria provided	literature only
New York Genome Center	RCV001255087	SCV001431178	uncertain significance	not provided	2019-12-06	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000606736	SCV001458253	pathogenic	Mitochondrial neurogastrointestinal encephalomyopathy	2020-09-16	no assertion criteria provided	clinical testing