ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1837C>T (p.His613Tyr) (rs147407423)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173762 SCV000224911 benign not specified 2015-04-02 criteria provided, single submitter clinical testing
GeneDx RCV000710183 SCV000242291 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The H613Y variant has been reported as a variant of uncertain clinical significance in two unrelated individuals with clinical features suggestive of POLG deficiency who were heterozygous for H613Y and did not have another identifiable POLG variant (Tang et al., 2011; Da Pozzo et al., 2017). One individual inherited the H613Y variant from an apparently unaffected father (Da Pozzo et al., 2017). The H613Y variant is observed in 134/24022 (0.56%) alleles from individuals of African background in large population cohorts, suggesting the variant is benign (Lek et al., 2016). The H613Y 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory,University of Chicago RCV000173762 SCV000596502 uncertain significance not specified 2015-12-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000173762 SCV000604902 uncertain significance not specified 2017-01-17 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710183 SCV000614708 uncertain significance not provided 2019-08-16 criteria provided, single submitter clinical testing
Invitae RCV000538134 SCV000630113 likely benign Progressive sclerosing poliodystrophy 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000717814 SCV000848674 uncertain significance Seizures 2018-04-26 criteria provided, single submitter clinical testing Insufficient evidence
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000538134 SCV000887100 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1837C>T (NP_002684.1:p.His613Tyr) [GRCH38: NC_000015.10:g.89325562G>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. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). 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 RCV000768055 SCV000898900 uncertain significance Progressive sclerosing poliodystrophy; 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 2017-09-05 criteria provided, single submitter clinical testing POLG NM_002693.2 exon10 p.His613Tyr (c.1837C>T): This variant has been reported in the literature in 1 individual with myopathy and abnormal neurological features (Da Pozzo 2017 PMID:28130605). This variant is present in 0.5% (134/24022) of African individuals in the Genome Aggregation Database ( This variant is present in ClinVar (Variation ID:193643). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. However, the variant Tyrosine (Tyr) amino acid is present in 2 other species (Chinese Softshell Turtle, Spiny Softshell Turtle), suggesting that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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