Submissions for variant NM_080916.3(DGUOK):c.4G>T (p.Ala2Ser)

gnomAD frequency: 0.00280  dbSNP: rs147551003

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173554	SCV000224676	uncertain significance	not provided	2018-04-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000173554	SCV000251319	likely benign	not provided	2020-11-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19748572, 18828154, 22622127, 17073823)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000173554	SCV000280759	uncertain significance	not provided	2016-01-18	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000173554	SCV000575220	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	DGUOK: BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000173554	SCV001012539	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000660620	SCV001135900	benign	Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000660620	SCV001297289	uncertain significance	Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000173554	SCV000802859	uncertain significance	not provided	2016-03-08	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000660620	SCV000986887	not provided	Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000173554	SCV001553284	likely benign	not provided		no assertion criteria provided	clinical testing	The DGUOK p.Ala2Ser variant was identified as a compound heterozygous variant in two pediatric cases with mitochondrial DNA depletion syndrome (Mousson_de_Camaret_2007_PMID: 17073823; Buchaklian_2012_PMID: 22622127). The variant was identified in dbSNP (ID: rs147551003) and ClinVar (classified as uncertain significance by Children's Mercy Hospital, GeneDx, Mayo Clinic, EGL Genetic Diagnostics, CeGaT Praxis; and as benign by Invitae and Mendelics). The variant was identified in control databases in 727 of 281762 chromosomes (3 homozygous) at a frequency of 0.00258 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 570 of 128878 chromosomes (freq: 0.004423), Latino in 91 of 35430 chromosomes (freq: 0.002568), Other in 16 of 7212 chromosomes (freq: 0.002219), Ashkenazi Jewish in 11 of 10352 chromosomes (freq: 0.001063), African in 22 of 24908 chromosomes (freq: 0.000883), South Asian in 14 of 30616 chromosomes (freq: 0.000457) and European (Finnish) in 3 of 24434 chromosomes (freq: 0.000123), but was not observed in the East Asian population. The p.Ala2 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000173554	SCV001742416	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000173554	SCV001923308	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000173554	SCV001974064	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003975258	SCV004790999	likely benign	DGUOK-related disorder	2021-11-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).