VCV000223064.41 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 223064 Accession: VCV000223064.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50526142 (GRCh38) [ NCBI UCSC ] 22: 50964571 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 5, 2016	Oct 20, 2024	Mar 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001953.5:c.1160-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001113755.3:c.1160-1G>A		splice acceptor
NM_001113756.3:c.1160-1G>A		splice acceptor
NM_001169109.2:c.-14+104G>A		intron variant
NM_001169110.1:c.-155G>A		5 prime UTR
NM_001257988.1:c.1160-1G>A		splice acceptor
NM_001257989.1:c.1174G>A	NP_001244918.1:p.Gly392Ser	missense
NC_000022.11:g.50526142C>T
NC_000022.10:g.50964571C>T
NG_011860.1:g.8944G>A
NG_016235.1:g.5298G>A
NG_021419.1:g.22927C>T
NG_202277.1:g.463C>T
LRG_727:g.8944G>A
LRG_727t1:c.1160-1G>A
LRG_727t2:c.1174G>A	LRG_727p2:p.Gly392Ser

... more HGVS ... less HGVS

Protein change

G392S

Other names

Canonical SPDI

NC_000022.11:50526141:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

Links

ClinGen: CA16616801 dbSNP: rs797044455 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LOC130067862	-	-	-	GRCh38	-	490
SCO2		-	-	GRCh38 GRCh37	4	884
TYMP		-	-	GRCh38 GRCh37	460	1108

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mitochondrial DNA depletion syndrome 1	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 21, 2024	RCV000208629.14
Mitochondrial neurogastrointestinal encephalomyopathy	Pathogenic (2)	criteria provided, single submitter	Aug 29, 2017	RCV000606736.13
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 7, 2023	RCV001255087.34

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 Affected status: yes Allele origin: germline	Department of Pathophysiology and Transplantation, University of Milan Accession: SCV001438019.1 First in ClinVar: Oct 20, 2020 Last updated: Oct 20, 2020	Publications: PubMed (1) PubMed: 19853446
Pathogenic (May 07, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367782.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3.
Pathogenic (Oct 07, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001578027.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 16199547‚ 9924029‚ 15781193‚ 10852545‚ 12529715 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001500762.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Mar 21, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207505.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Aug 29, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Mitochondrial neurogastrointestinal encephalomyopathy (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000731948.2 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (2) PubMed: 10852545‚ 12529715 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Jan 14, 2016)	no assertion criteria provided Method: literature only	Mitochondrial DNA depletion syndrome 1 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000264546.1 First in ClinVar: Mar 05, 2016 Last updated: Mar 05, 2016	Publications: PubMed (1) PubMed: 10852545 Other databases http://www.ncbi.nlm.nih.gov/book… http://www.ncbi.nlm.nih.gov/books/NBK1179/
Uncertain significance (Dec 06, 2019)	no assertion criteria provided Method: clinical testing	Not provided Affected status: yes Allele origin: germline	New York Genome Center Accession: SCV001431178.2 First in ClinVar: Sep 05, 2020 Last updated: Sep 05, 2020	Secondary finding: no Method: whole genome sequencing
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Mitochondrial neurogastrointestinal encephalomyopathy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458253.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mitochondrial Neurogastrointestinal Encephalopathy Disease.	Adam MP	-	2016	PMID: 20301358
Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity.	Massa R	Neuromuscular disorders : NMD	2009	PMID: 19853446
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome.	Slama A	Molecular genetics and metabolism	2005	PMID: 15781193
Four novel thymidine phosphorylase gene mutations in mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) patients.	Kocaefe YC	European journal of human genetics : EJHG	2003	PMID: 12529715
Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.	Nishino I	Annals of neurology	2000	PMID: 10852545
Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.	Nishino I	Science (New York, N.Y.)	1999	PMID: 9924029

Text-mined citations for rs797044455 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs797044455 ...