ClinVar Genomic variation as it relates to human health

Identified in an individual with developmental delay, hypotonia, muscle weakness, regression, respiratory failure, hyporeflexia, dysphagia, and seizures, who was also heterozygous for another variant in TK2 (PMID: 29735374); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 32573669, 29735374)

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial DNA depletion syndrome 2 (myopathic type) (MIM#609560). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM, GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). However, it should be noted that a single nucleotide change that results in the same protein outcome (c.373C>T; p.(Gln125X)) as our variant has 2 heterozygotes in gnomAD v2. (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least five NMD-predicted variants that have been classified as likely pathogenic or pathogenic (ClinVar, DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individual. This variant has been reported in two individuals with mtDNA depletion syndrome (ClinVar, PMID: 29735374). It should also be noted that a reported single nucleotide change that results in the same protein outcome as our variant (c.373C>T; p.(Gln125X)) has been identified in individuals with mtDNA depletion syndrome (PMIDs: 16908738, 29602790). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change creates a premature translational stop signal (p.Gln125*) in the TK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TK2 are known to be pathogenic (PMID: 20421844). 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 premature translational stop signal has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 29735374). ClinVar contains an entry for this variant (Variation ID: 265614). For these reasons, this variant has been classified as Pathogenic.