Submissions for variant NM_080916.3(DGUOK):c.462T>A (p.Asn154Lys)

gnomAD frequency: 0.00021  dbSNP: rs144181978

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195764	SCV000251324	likely pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23043144, 30956829, 29228108, 30283818, 30393377, 32308999, 33513296, 35114397, 31664448, 29137425)
Revvity Omics, Revvity	RCV000195764	SCV002024069	likely pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195764	SCV002138148	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 154 of the DGUOK protein (p.Asn154Lys). This variant is present in population databases (rs144181978, gnomAD 0.03%). This missense change has been observed in individual(s) with DGUOK-related conditions (PMID: 23043144, 29228108, 30283818, 30956829, 31664448). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 214285). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DGUOK protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000195764	SCV002520018	likely pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3, PS4_moderate
Ambry Genetics	RCV002517206	SCV003667811	pathogenic	Inborn genetic diseases	2022-10-18	criteria provided, single submitter	clinical testing	The c.462T>A (p.N154K) alteration is located in exon 4 (coding exon 4) of the DGUOK gene. This alteration results from a T to A substitution at nucleotide position 462, causing the asparagine (N) at amino acid position 154 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.014% (40/282882) total alleles studied. The highest observed frequency was 0.029% (37/129192) of European (non-Finnish) alleles. This alteration has been reported with a second DGUOK variant in multiple individuals with progressive external ophthalmoplegia and other features of adult-onset mitochondrial DNA depletion syndrome (Ronchi, 2012; Caporali, 2018; Komal, 2018; Montano, 2019). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235120	SCV003934073	pathogenic	Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: DGUOK c.462T>A (p.Asn154Lys) results in a non-conservative amino acid change located in the deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251492 control chromosomes (gnomAD). c.462T>A has been reported in the literature in the compound heterozygous state in at least six individuals with multiple mitochondrial DNA deletions and primarily presenting with progressive external ophthalmoplegia and myopathy (e.g. Ronchi_2012, Komal_2018, Caporali_2018, Montano_2019, Goudenege_2019). These data indicate that the variant is very likely to be associated with Mitochondrial DNA depletion syndrome 3. 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: 28902392, 30393377, 31664448, 30956829, 23043144, 30283818 , 29228108 ). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=3)/likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000239593	SCV000297862	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4	2016-08-18	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000195764	SCV000705911	uncertain significance	not provided	2017-10-12	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895259	SCV004713973	pathogenic	DGUOK-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The DGUOK c.462T>A variant is predicted to result in the amino acid substitution p.Asn154Lys. This variant was reported in the compound heterozygous state in three unrelated individuals presenting with late-onset progressive external ophthalmoplegia (Patients 1 and 2 in Ronchi et al. 2012. PubMed ID: 23043144; Montano et al. 2019. PubMed ID: 30956829). Analysis of muscle tissues of the patients from Ronchi et al. showed a severe defect in DGUOK activity (Ronchi et al. 2012. PubMed ID: 23043144). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.