16-66531394-GC-TT

Variant names:

• chr16-66531394-GC-TT
• rs281865507
• NM_004614.5:c.360_361delGCinsAA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_004614.5(TK2):​c.360_361delGCinsAA​(p.His121Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R120R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TK2 NM_004614.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.48
• Publications: 1 publications found

Genes affected

TK2 (HGNC:11831): (thymidine kinase 2) This gene encodes a deoxyribonucleoside kinase that specifically phosphorylates thymidine, deoxycytidine, and deoxyuridine. The encoded enzyme localizes to the mitochondria and is required for mitochondrial DNA synthesis. Mutations in this gene are associated with a myopathic form of mitochondrial DNA depletion syndrome. Alternate splicing results in multiple transcript variants encoding distinct isoforms, some of which lack transit peptide, so are not localized to mitochondria. [provided by RefSeq, Dec 2012]

TK2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome, myopathic form

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_004614.5
• PP5: Variant 16-66531394-GC-TT is Pathogenic according to our data. Variant chr16-66531394-GC-TT is described in ClinVar as [Pathogenic]. Clinvar id is 38986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5	c.360_361delGCinsAA	p.His121Asn	missense_variant		ENST00000544898.6	NP_004605.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6	c.360_361delGCinsAA	p.His121Asn	missense_variant		1	NM_004614.5	ENSP00000440898.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome Pathogenic:1

Feb 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TK2 c.360_361delinsAA (p.His121Asn) results in a conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250910 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.360_361delinsAA has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (Saada_2001, Oskoui_2006, Jou_2019, etc.). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Saada_2001, Wang_2003). One ClinVar submitter has submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 121 of the TK2 protein (p.His121Asn). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 11687801, 12391347, 16908738, 29602790). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His90Asn. ClinVar contains an entry for this variant (Variation ID: 38986). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TK2 function (PMID: 12493767, 18446447). For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial DNA depletion syndrome, myopathic form;C4310734:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 Pathogenic:1

Jan 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=0/100	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs281865507; hg19: chr16-66565297;