chr15-89330258-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_002693.3(POLG):ā€‹c.678G>Cā€‹(p.Gln226His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,611,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 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: š‘“ 0.00052 ( 0 hom., cov: 32)
Exomes š‘“: 0.00053 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

2
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:6

Conservation

PhyloP100: 1.16
Variant links:
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]
POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07381511).
BP6
Variant 15-89330258-C-G is Benign according to our data. Variant chr15-89330258-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206581.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=9}. Variant chr15-89330258-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLGNM_002693.3 linkuse as main transcriptc.678G>C p.Gln226His missense_variant 3/23 ENST00000268124.11 NP_002684.1
POLGARFNM_001406557.1 linkuse as main transcriptc.733G>C p.Ala245Pro missense_variant 3/23 NP_001393486.1
POLGNM_001126131.2 linkuse as main transcriptc.678G>C p.Gln226His missense_variant 3/23 NP_001119603.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkuse as main transcriptc.678G>C p.Gln226His missense_variant 3/231 NM_002693.3 ENSP00000268124 P1
POLGARFENST00000706918.1 linkuse as main transcriptc.733G>C p.Ala245Pro missense_variant 2/2 ENSP00000516626 P1

Frequencies

GnomAD3 genomes
AF:
0.000519
AC:
79
AN:
152256
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000723
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000896
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000408
AC:
101
AN:
247722
Hom.:
0
AF XY:
0.000409
AC XY:
55
AN XY:
134464
show subpopulations
Gnomad AFR exome
AF:
0.000126
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000340
Gnomad NFE exome
AF:
0.000770
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000526
AC:
768
AN:
1459374
Hom.:
0
Cov.:
32
AF XY:
0.000519
AC XY:
377
AN XY:
726014
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000367
Gnomad4 NFE exome
AF:
0.000639
Gnomad4 OTH exome
AF:
0.000481
GnomAD4 genome
AF:
0.000519
AC:
79
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.000497
AC XY:
37
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000896
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000578
Hom.:
0
Bravo
AF:
0.000457
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000387
AC:
47
EpiCase
AF:
0.000436
EpiControl
AF:
0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:4
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsOct 27, 2021- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 27, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18156159, 21880868, 33600046) -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 28, 2022- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024POLG: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 14, 2018- -
Progressive sclerosing poliodystrophy Benign:2
Likely benign, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineOct 01, 2018The NM_002693.2:c.678G>C (NP_002684.1:p.Gln226His) [GRCH38: NC_000015.10:g.89330258C>G] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). 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. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 05, 2023Variant summary: POLG c.678G>C (p.Gln226His) results in a non-conservative amino acid change located in the exonuclease domain (IPR041336) of 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 0.00041 in 247722 control chromosomes (gnomAD). c.678G>C has been reported in the literature in individuals affected with POLG-Related Spectrum Disorders, including parkinsonism (Montaut_2018) and adult-onset chronic progressive external ophthalmoplegia (Heighton_2019) without strong evidence for causality, and as a compound heterozygous genotype together with a pathogenic variant in an individual diagnosed with sensory ataxic neuropathy with mtDNA deletions (Keller_2021). These data do not allow any conclusion about variant significance. 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: 31521625, 33600046, 29913018). Twelve submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant with conflicting assessments: VUS (n=9), likely benign (n=2), likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
POLG-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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 submitterclinical testingCentogene AG - the Rare Disease CompanyJun 05, 2019- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 17, 2021The c.678G>C (p.Q226H) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 678, causing the glutamine (Q) at amino acid position 226 to be replaced by a histidine (H). The p.Q226H alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Uncertain:1
Uncertain significance, criteria provided, single submitterresearchInstitute of Human Genetics, Cologne UniversityJan 30, 2024- -
POLG-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 05, 2024The POLG c.678G>C variant is predicted to result in the amino acid substitution p.Gln226His. This variant has been reported in the compound heterozygous state in an individual with infantile muscular atrophy and weakness (Keller et al. 2021. PubMed ID: 33600046). Additionally, this variant was reported in the heterozygous state in one patient with clinical features suggestive of POLG deficiency, although a second plausible causative variant was not identified (Tang et al. 2011. PubMed ID: 21880868, Supplementary Table 3). This variant is reported in 0.076% 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. -
Autism;C0036572:Seizure Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalAug 10, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
24
DANN
Uncertain
0.98
Eigen
Benign
-0.23
Eigen_PC
Benign
0.028
FATHMM_MKL
Uncertain
0.93
D
M_CAP
Benign
0.051
D
MetaRNN
Benign
0.074
T
MutationTaster
Benign
1.0
N;N
ClinPred
0.032
T
GERP RS
4.8
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147282197; hg19: chr15-89873489; API