ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3131T>C (p.Val1044Ala) (rs150233690)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000118016 SCV000152334 uncertain significance not provided 2014-03-24 criteria provided, single submitter clinical testing
GeneDx RCV000118016 SCV000242225 uncertain significance not provided 2018-11-26 criteria provided, single submitter clinical testing The V1044A variant in the POLG gene has been reported previously in an individual with severe encephalopathy, intractable epilepsy, an athetoid-ataxic movement disorder, and developmental regression, who also harbored a second variant in the POLG gene that was reported to be in trans (Isohanni et al., 2011). This variant was also reported in a patient with mtDNA depletion syndrome with liver fibrosis and portal hypertension, and two other POLG variants with unknown phase (Stalke et al., 2017). The V1044A variant is observed in 112/126,620 alleles (0.089%) from individuals of non-Finnish European background, and 163/277,104 global alleles (0.059%) with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). However, the V1044A variant is a conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Valine are tolerated across species. Additionally, in silico analysis predicts that the V1044A variant likely does not alter the protein structure/function. We therefore interpret V1044A as a variant of uncertain significance.
Invitae RCV000234341 SCV000287671 uncertain significance Progressive sclerosing poliodystrophy 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1044 of the POLG protein (p.Val1044Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs150233690, ExAC 0.09%). This variant has been reported in an individual affected with Alpers-like phenotype who also had a second missense variant (p.R722H), as well as in an individual with developmental delay, hypotonia, encephalopathy, and intractable seizure in the heterozygous state without finding a second variant (PMID: 21357833, 21880868). This variant was also observed in an individual with atypical mitochondrial DNA depletion syndrome (PMID: 28776642). ClinVar contains an entry for this variant (Variation ID: 129994). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000515366 SCV000611503 uncertain significance Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Cerebellar ataxia infantile with progressive external ophthalmoplegia; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2017-05-23 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000118016 SCV000614720 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000118016 SCV000705798 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000720436 SCV000851313 uncertain significance Seizures 2019-04-09 criteria provided, single submitter clinical testing Insufficient evidence
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000234341 SCV000887299 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3131T>C (NP_002684.1:p.Val1044Ala) [GRCH38: NC_000015.10:g.89319073A>G] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21357833 . This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000778452 SCV000914700 uncertain significance POLG-Related Spectrum Disorders 2018-11-15 criteria provided, single submitter clinical testing The POLG c.3131T>C (p.Val1044Ala) has been reported in four studies and in a total of five patients including one in a compound heterozygous state, and four in a heterozygous state (Isohanni et al. 2011; Tang et al. 2011; Stalke et al. 2018; Traboulsee et al. 2017). Two of the individuals identified with the variant have multiple sclerosis, two have mitochondrial disease, and the fifth was noted to have POLG-deficiency (Isohanni et al. 2011; Tang et al. 2011; Stalke et al. 2018; Traboulsee et al. 2017). The p.Val1044Ala variant was found in one control out of 1200 control individuals and is reported at a frequency of 0.003319 in the Other population of the Exome Aggregation Consortium. Based on the evidence, the p.Val1044Ala is classified as a variant of unknown significance, but suspicious for pathogenicity for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000118016 SCV001149558 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678829 SCV000805015 uncertain significance EEG abnormality 2016-12-22 no assertion criteria provided clinical testing

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