ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.328C>T (p.His110Tyr) (rs139599587)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727081 SCV000242309 uncertain significance not provided 2019-01-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The H110Y variant has been reported previously in a female with hypotonia, failure to thrive, and short stature who did not have a second detectable variant in the POLG gene (Wong et al., 2008). The H110Y variant is observed in 19/23260 (0.08%) alleles from individuals of African background (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000461638 SCV000543880 uncertain significance Progressive sclerosing poliodystrophy 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 110 of the POLG protein (p.His110Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs139599587, ExAC 0.09%). This variant has been reported in an individual with hypotonia, failure to thrive and short stature (PMID: 18546365). This variant has also been observed in an individual affected with progressive external ophthalmoplegia (PMID: 27826120). ClinVar contains an entry for this variant (Variation ID: 206619). Experimental evidence in a yeast model system shows this variant behaves similarly to the wild type POLG protein (PMID: 20185557). In summary, this variant is a rare missense change that showed no impact on protein function in one study. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727081 SCV000705481 uncertain significance not provided 2017-01-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000720040 SCV000850916 uncertain significance Seizures 2019-09-04 criteria provided, single submitter clinical testing The p.H110Y variant (also known as c.328C>T), located in coding exon 1 of the POLG gene, results from a C to T substitution at nucleotide position 328. The histidine at codon 110 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in a three year old patient with some features of Alpers syndrome and in an eleven year old girl with CPEO plus syndrome (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72; Sonam K et al. Mitochondrion, 2017 Jan;32:42-49). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000461638 SCV000887181 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.328C>T (NP_002684.1:p.His110Tyr) [GRCH38: NC_000015.10:g.89333427G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BS3:Well-established functional studies show no deleterious effect. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768048 SCV000898893 uncertain significance Progressive sclerosing poliodystrophy; Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-29 criteria provided, single submitter clinical testing POLG NM_002693.2 exon 2 p.His110Tyr (c.328C>T): This variant has been reported in the literature in 1 individual with features of Alpers syndrome (hypotonia, failure to thrive, short stature and respiratory failure) (Wong 2008 PMID:18546365). This variant is present in 0.07% (19/24074) of African alleles in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:206619). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Functional studies involving yeast suggest that this variant may not impact the protein (Stumpf 2010 PMID:20185557). However, these studies may not accurately represent human biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mayo Clinic Laboratories, Mayo Clinic RCV000727081 SCV001716246 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing

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