15-89327198-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4
The NM_002693.3(POLG):āc.1402A>Gā(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N468S) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.1402A>G | p.Asn468Asp | missense_variant | 7/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*674A>G | 3_prime_UTR_variant | 7/23 | |||
POLG | NM_001126131.2 | c.1402A>G | p.Asn468Asp | missense_variant | 7/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.1402A>G | p.Asn468Asp | missense_variant | 7/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000624 AC: 95AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000473 AC: 119AN: 251488Hom.: 0 AF XY: 0.000456 AC XY: 62AN XY: 135920
GnomAD4 exome AF: 0.000829 AC: 1212AN: 1461886Hom.: 1 Cov.: 34 AF XY: 0.000792 AC XY: 576AN XY: 727244
GnomAD4 genome AF: 0.000624 AC: 95AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.000738 AC XY: 55AN XY: 74500
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:6
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 | Jul 01, 2022 | 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 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2023 | 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 (Luoma Pet al., 2004; Wanrooij S et al., 2004); Identified as homozygous in an infant with Aicardi-Goutires syndrome who was also homozygous for a pathogenic variant in TREX (Tise CG et al., 2021); In silico analysis supports 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, 15351195, 33683010, 35641312) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 02, 2023 | - - |
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 | Mayo Clinic Laboratories, Mayo Clinic | Jun 09, 2023 | - - |
Progressive sclerosing poliodystrophy Pathogenic:2Benign:1
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 pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 24, 2022 | - - |
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]. - |
Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | 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 (119/251488 control chromosomes). 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 is likely to 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). 19 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 submitters classified the variant as LP/P, 1 as LB and 15 as VUS). Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. - |
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 | - - |
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. - |
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. - |
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 | - - |
Seizure;C3714756:Intellectual disability Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 07, 2020 | - - |
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at