ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1174C>G (p.Leu392Val) (rs145289229)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720206 SCV000851083 likely benign Seizures 2017-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Co-occurence with mutation in same gene (phase unknown),Subpopulation frequency in support of benign classification
Athena Diagnostics Inc RCV000710181 SCV000614699 likely benign not provided 2018-08-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188651 SCV000231656 likely benign not specified 2018-04-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515415 SCV000611501 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, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000188651 SCV000242274 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The L392V missense change was previously identified in cis with another POLG variant in an individual with Parkinson disease and in several unaffected control individuals (Luoma et al., 2007). L392V was subsequently reported on the same allele (in cis) with an in-frame duplication (c.3240_3242dupCCG reported as p.R1081dup) in an individual with Alpers disease who had another POLG pathogenic variant on the other allele (Cardenas et al., 2010). L392V has also been identified in multiple individuals with clinical features of a POLG disorder who did not have a second identifiable pathogenic variant, suggesting it may be a benign variant (Wong et al., 2008; Tang et al., 2011). The L392V variant is observed in 48/6576 (0.7%) alleles from individuals of Finnish background, including a homozygous individual, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution alters a position that is highly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000475753 SCV000556247 likely benign Progressive sclerosing poliodystrophy 2017-12-20 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000475753 SCV000887092 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1174C>G (NP_002684.1:p.Leu392Val) [GRCH38: NC_000015.10:g.89328532G>C] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:20434700 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.

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