rs145843073
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4
The NM_002693.3(POLG):c.1402A>G(p.Asn468Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,614,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00083 ( 1 hom. )
Consequence
POLG
NM_002693.3 missense
NM_002693.3 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 2.97
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP5
Variant 15-89327198-T-C is Pathogenic according to our data. Variant chr15-89327198-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206596.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_benign=1, Uncertain_significance=16, Pathogenic=1, Likely_pathogenic=4}. Variant chr15-89327198-T-C is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.024409533). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POLG | NM_002693.3 | c.1402A>G | p.Asn468Asp | missense_variant | 7/23 | ENST00000268124.11 | NP_002684.1 | |
| POLG | NM_001126131.2 | c.1402A>G | p.Asn468Asp | missense_variant | 7/23 | NP_001119603.1 | ||
| POLGARF | NM_001406557.1 | c.*674A>G | 3_prime_UTR_variant | 7/23 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| POLG | ENST00000268124.11 | c.1402A>G | p.Asn468Asp | missense_variant | 7/23 | 1 | NM_002693.3 | ENSP00000268124.5 |
Frequencies
GnomAD3 genomes 0.000624 AC: 95AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000473 AC: 119AN: 251488Hom.: 0 AF XY: 0.000456 AC XY: 62AN XY: 135920
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GnomAD4 exome AF: 0.000829 AC: 1212AN: 1461886Hom.: 1 Cov.: 34 AF XY: 0.000792 AC XY: 576AN XY: 727244
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GnomAD4 genome 0.000624 AC: 95AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.000738 AC XY: 55AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:17Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:6
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2024 | Identified in three members of a family with CPEO, peripheral neuropathy, parkinsonism, and multiple mtDNA deletions in muscle who were also heterozygous for another POLG variant on the other allele; the authors could not conclusively determine whether p.(N468D) was related to the phenotype as siblings carrying p.(N468D) were unaffected (PMID: 15351195, 15181170); Identified as homozygous in an infant with Aicardi-Goutires syndrome who was also homozygous for a pathogenic variant in TREX1 (PMID: 33683010); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24122062, 19578034, 24508722, 28284481, 31669236, 32391929, 32347949, 29029963, 29712893, 16401742, 24259288, 21880868, 34426522, 22647225, 23811324, 19752458, 15181170, 32234506, 33513296, 23921535, 35114397, 36291626, 33683010, 35641312, 15351195, 24331360, 25193669, 31658717, 23426270, 30373890, 30255931, 29997391, 37138020) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | May 20, 2022 | PM3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 12, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. Computational tools disagree on the variant's effect on normal protein function. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 09, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 17, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | POLG: PM2:Supporting, BP4 - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 02, 2023 | - - |
Progressive sclerosing poliodystrophy Pathogenic:2Benign:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 01, 2018 | The NM_002693.2:c.1402A>G (NP_002684.1:p.Asn468Asp) [GRCH38: NC_000015.10:g.89327198T>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15351195 ; 16401742 . This variant meets the following evidence codes reported in the ACMG-guideline. PS4:Prevalence of variant in affecteds statistically increased over controls. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 04, 2020 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 24, 2022 | - - |
POLG-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2024 | The POLG c.1402A>G variant is predicted to result in the amino acid substitution p.Asn468Asp. This variant has been reported in individuals with autosomal recessive POLG-related mitochondrial disease (Palin et al. 2013. PubMed ID: 23811324; Luoma et al. 2004. PubMed ID: 15351195; Woodbridge et al. 2013. PubMed ID: 22647225; González-Vioque et al. 2006. PubMed ID: 16401742; Buzkova et al. 2018. PubMed ID: 30373890). Some POLG variants have also been implicated in autosomal dominant progressive external ophthalmoplegia (PEO), and several PEO patients have been reported to carry this variant in the heterozygous state (Schulte et al. 2009. PubMed ID: 19752458). However, in a second family, heterozygous carriers of the c.1402A>G (p.Asn468Asp) variant were reportedly asymptomatic (Luoma et al. 2004. PubMed ID: 15351195). In ClinVar, this variant has conflicting interpretations of uncertain, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/206596/). This variant is reported in 0.072% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic for autosomal recessive disease. - |
Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 01, 2021 | The POLG c.1402A>G; p.Asn468Asp variant is reported in the literature in individuals affected with autosomal recessive progressive external ophthalmoplegia (Luoma 2004, Palin 2013, Woodbridge 2013). The affected individuals identified in these reports were compound heterozygous for the p.Asn468Asp variant while heterozygous carriers in the same family were unaffected. The variant has also been shown to co-segregate with disease in families with autosomal recessive progressive external ophthalmoplegia (Wanrooij 2004). This variant is reported with conflicting interpretations in ClinVar (Variation ID: 206596). Another variant in this region, p.Ala467Thr, is considered the most common pathogenic POLG variant (Variation ID: 13496). However, due to limited functional evidence, the clinical significance of the p.Asn468Asp variant is uncertain. - |
POLG-Related Spectrum Disorders Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 24, 2022 | The c.1402A>G (p.N468D) alteration is located in exon 7 (coding exon 6) of the POLG gene. This alteration results from a A to G substitution at nucleotide position 1402, causing the asparagine (N) at amino acid position 468 to be replaced by an aspartic acid (D). The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.N468 amino acid is not conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.N468D alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Lennox-Gastaut syndrome Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Dec 05, 2016 | - - |
Hereditary spastic paraplegia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 01, 2020 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2024 | Variant summary: POLG c.1402A>G (p.Asn468Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251488 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders, allowing no conclusion about variant significance. c.1402A>G has been reported in the literature in individuals affected with variety of POLG-related phenotypes. The variant has been reported in three affected family members (and no unaffected family members) with progressive external ophthalmoplegia and parkinsonism as well as a patient with early onset Parkinson's disease, all with a second variant of unknown significance (Luoma_2004, Ylonen_2017). Additionally, the variant was reported along with a pathogenic variant in cases of progressive external ophthalmoplegia and tetraparesis and mitochondrial neurogastrointestinal encephalopathy (Gonzalez-Vioque_2006, Woodbridge_2013). The variant has also been reported in the homozygous state in a patient with congenital ataxia who had no features suggestive of a POLG-related phenotype, therefore ITPR1 variants were considered resposible for congenital ataxia in this patient (Valence_2019). These data indicate that the variant may be associated with disease. 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: 31658717, 16401742, 15351195, 15181170, 22647225, 29029963, 29997391). ClinVar contains an entry for this variant (Variation ID: 206596). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Mitochondrial disease Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Variants in the centre of motif B in the polymerase domain (highly conserved active site), result in dominant disease (PMID: 28480171). (N) 0200 - Variant is predicted to result in a missense amino acid change from an asparagine to an aspartate (exon 7). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (138 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (6 heterozygotes, 0 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. It has been reported as compound heterozygous with another variant in patients with progressive external ophthalmoplegia. However, it has been classified as both pathogenic and VUS in ClinVar (PMID: 22647225, 16401742). (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jan 28, 2022 | - - |
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | POLG NM_002693.2 exon 7 p.Asn468Asp (c.1402A>G): This variant has been reported in the literature in the compound heterozygous state in at least 3 individuals with autosomal recessive progressive external opthalmoplegia in addition to ataxia, tetraparesis, and/or parkinsonism, segregating with disease in two affected family members (Luoma 2004 PMID:15351195, Gonzalez-Viogue 2006 PMID:16401742, Woodbridge 2013 PMID:22647225). This variant has also been identified in multiple individuals with suspected POLG-deficiency who did not have a second identifiable variant in the POLG gene (Blok 2009 PMID:19578034, Tang 2011 PMID:21880868). This variant is present in 0.07% (18/25122) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-89870429-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:206596). This variant amino acid Aspartic Acid (Asp) is present in several species including two mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Computational scores
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Name
Calibrated prediction
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AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at