rs139599587
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_002693.3(POLG):c.328C>T(p.His110Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000846 in 1,608,446 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000065 ( 1 hom. )
Consequence
POLG
NM_002693.3 missense
NM_002693.3 missense
Scores
5
2
3
Clinical Significance
Conservation
PhyloP100: 9.59
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 -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.26894468).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.328C>T | p.His110Tyr | missense_variant | 2/23 | ENST00000268124.11 | NP_002684.1 | |
POLG | NM_001126131.2 | c.328C>T | p.His110Tyr | missense_variant | 2/23 | NP_001119603.1 | ||
POLGARF | NM_001406557.1 | c.383C>T | p.Ala128Val | missense_variant | 2/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.328C>T | p.His110Tyr | missense_variant | 2/23 | 1 | NM_002693.3 | ENSP00000268124.5 | ||
POLGARF | ENST00000706918.1 | c.383C>T | p.Ala128Val | missense_variant | 1/2 | ENSP00000516626.1 |
Frequencies
GnomAD3 genomes AF: 0.000282 AC: 43AN: 152274Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000180 AC: 43AN: 238934Hom.: 0 AF XY: 0.000183 AC XY: 24AN XY: 130928
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GnomAD4 exome AF: 0.0000646 AC: 94AN: 1456054Hom.: 1 Cov.: 32 AF XY: 0.0000731 AC XY: 53AN XY: 724656
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GnomAD4 genome AF: 0.000276 AC: 42AN: 152392Hom.: 0 Cov.: 34 AF XY: 0.000268 AC XY: 20AN XY: 74520
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 28, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 22, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 01, 2024 | Reported previously in a female with hypotonia, failure to thrive, and short stature who did not have a second detectable variant in the POLG gene (PMID: 18546365); Reported previously in the heterozygous state in a child with chronic progressive external ophthalmoplegia and complex I deficiency with no second variant identified; however, segregation information was not provided (PMID: 27826120); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18546365, 20185557, 33469851, 32348839, 28480171, 30214008, 26934580, 27826120) - |
Progressive sclerosing poliodystrophy Uncertain:1Benign:1
Benign, 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.328C>T (NP_002684.1:p.His110Tyr) [GRCH38: NC_000015.10:g.89333427G>A] variant in POLG gene is interpretated to be a 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). BS3:Well-established functional studies show no deleterious effect. Based on the evidence criteria codes applied, the variant is suggested to be Benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 12, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 110 of the POLG protein (p.His110Tyr). This variant is present in population databases (rs139599587, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365, 27826120). ClinVar contains an entry for this variant (Variation ID: 206619). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function. Experimental studies have shown that this missense change does not substantially affect POLG function (PMID: 20185557). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2021 | Variant summary: POLG c.328C>T (p.His110Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 238934 control chromosomes (gnomAD). c.328C>T has been reported in the literature in individuals affected with features of Alpers syndrome, chronic progressive external ophthalmoplegia and sensory ataxic neuropathy with cerebellar syndrome (Wong_2008, Sonam_2017, Deepha_2021). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. Experimental evidence evaluating an impact on protein function in yeast assays, demonstrated the variant to function similarly to wild-type (Stumpf_2010). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 04, 2019 | The p.H110Y variant (also known as c.328C>T), located in coding exon 1 of the POLG gene, results from a C to T substitution at nucleotide position 328. The histidine at codon 110 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in a three year old patient with some features of Alpers syndrome and in an eleven year old girl with CPEO plus syndrome (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72; Sonam K et al. Mitochondrion, 2017 Jan;32:42-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 2 p.His110Tyr (c.328C>T): This variant has been reported in the literature in 1 individual with features of Alpers syndrome (hypotonia, failure to thrive, short stature and respiratory failure) (Wong 2008 PMID:18546365). This variant is present in 0.07% (19/24074) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-89876658-G-A). This variant is present in ClinVar (Variation ID:206619). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Functional studies involving yeast suggest that this variant may not impact the protein (Stumpf 2010 PMID:20185557). However, these studies may not accurately represent human biological function. 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
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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