ClinVar Genomic variation as it relates to human health

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.

Variant summary: POLG c.3131T>C (p.Val1044Ala) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 251418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders (0.00065 vs 0.0035), allowing no conclusion about variant significance. c.3131T>C has been reported in the literature as a compound heterozygous genotype in an individual with an Alpers-like phenotype (Isohanni_2011), in the heterozygous state together with other POLG variants (phase unspecified) in an individual suspected of an atypical mitochondrial DNA depletion syndrome presenting with liver fibrosis with portal hypertension (Stalke_2018), and as an uninformative genotype (i.e. zygosity not specified) in at least one individual from a cohort of patients with POLG-related disorders (Hkitmat_2020). It has also been reported in a case-control study in two individuals affected with multiple sclerosis, but was also found in one control individual (Traboulsee_2017). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32391929, 21357833, 28776642, 28337550). Fifteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS, and one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

The c.3131T>C (p.V1044A) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 3131, causing the valine (V) at amino acid position 1044 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Reported previously in an individual with severe encephalopathy, intractable epilepsy, an athetoid-ataxic movement disorder, and developmental regression, who also harbored a second POLG variant on the opposite allele. Please note that this second POLG variant is classified as benign by GeneDx (PMID: 21357833); Reported in a patient with mtDNA depletion syndrome with liver fibrosis and portal hypertension, and two other POLG variants with unknown phase (PMID: 28776642); Reported in a child with developmental delay, hypotonia, encephalopathy, seizure, intractable seizure, muscle weakness, gastrointestinal reflux in whom a second POLG variant was not described (PMID: 21880868); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28337550, 34426522, Singh2021[Poster], 32391929, 28776642, 21357833, 21880868)

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.

The POLG c.3131T>C variant is predicted to result in the amino acid substitution p.Val1044Ala. This variant has been reported in the compound heterozygous state with another polymorphic variant in a patient with Alpers-like phenotype; however, the pathogenicity of this variant was not established (Isohanni et al. 2011. PubMed ID: 21357833). The c.3131T>C variant was also detected, along with another missense variant and a 5’ UTR variant, in an individual with liver fibrosis with portal hypertension (Stalke et al. 2018. PubMed ID: 28776642). Additionally, this variant was reported in the heterozygous state in a patient who presented with developmental delay, hypotonia, encephalopathy, seizure, and gastrointestinal reflux (Tang et al. 2011. PubMed ID: 21880868), as well as in a cohort of patients who presented with suspected multiple sclerosis (Traboulsee et al. 2017. PubMed ID: 28337550); however, in the latter study, this variant was also identified in an unaffected control. This variant is reported in 0.088% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.