rs113994094
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4
The NM_002693.3(POLG):c.752C>T(p.Thr251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,613,784 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POLG | NM_002693.3 | c.752C>T | p.Thr251Ile | missense_variant | Exon 3 of 23 | ENST00000268124.11 | NP_002684.1 | |
| POLG | NM_001126131.2 | c.752C>T | p.Thr251Ile | missense_variant | Exon 3 of 23 | NP_001119603.1 | ||
| POLGARF | NM_001430120.1 | c.*24C>T | downstream_gene_variant | NP_001417049.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| POLG | ENST00000268124.11 | c.752C>T | p.Thr251Ile | missense_variant | Exon 3 of 23 | 1 | NM_002693.3 | ENSP00000268124.5 | ||
| POLGARF | ENST00000706918.1 | c.*24C>T | downstream_gene_variant | ENSP00000516626.1 |
Frequencies
GnomAD3 genomes 0.00152 AC: 232AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00155 AC: 389AN: 251268Hom.: 1 AF XY: 0.00161 AC XY: 219AN XY: 135894
GnomAD4 exome AF: 0.00203 AC: 2965AN: 1461440Hom.: 2 Cov.: 32 AF XY: 0.00197 AC XY: 1429AN XY: 727040
GnomAD4 genome 0.00152 AC: 232AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104AN XY: 74492
ClinVar
Submissions by phenotype
not provided Pathogenic:11Uncertain:1
- -
PM3_strong, PS3, PS4 -
POLG: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
- -
The T251I missense variant in the POLG gene has been reported previously in association with several POLG-related disorders (Human DNA Polymerase Gamma Mutation Database). The T251I missense variant is typically found on the same allele (in cis) with the P587L variant and together they account for approximately 6% of disease-causing alleles in the POLG gene (Tang et al., 2011); however, the P587L variant was not observed in this patient. The T251I variant is observed in 195/66,122 (0.3%) alleles from individuals of European background, including 1 unrelated homozygous individual in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T251I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution alters at a poorly conserved residue predicted to be in the exonuclease domain. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret T251I as a pathogenic variant. -
Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. -
- -
- -
- -
- -
- -
- -
Progressive sclerosing poliodystrophy Pathogenic:7Uncertain:3
- -
The missense p.Thr251Ile has been previously reported in multiple studies with p.Pro587Leu and and reported as disease-causing alleles in patients with POLG-related diseases with a wide range of phenotypes [PMIDs: 25660390, 21880868, 19189930, 16621917, 14635118 and 15349879]. In addition, these two variants were found to be in-cis and co-segregated with disease phenotype in several families [PMID: 25660390, 19189930]. Additionally, in-vitro biochemical characterization showed that individually both p.Thr251Ile and p.Pro587Leu substitutions functionally impair pol γ activity. However, results also suggest a synergistic effect in terms of impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity in the double mutant cells suggesting the pathogenicity of these variants [PMID: 28154168]. The heterozygous p.T251I+p.P587L (cis) allele reported to be associated with a relatively mild phenotype and reported as most common recessive mutation in POLG-related phenotypes [PMID: 18546365, 15689359]. -
- -
- -
- -
This variant was identified as compound heterozygous. -
- -
The NM_002693.2:c.752C>T (NP_002684.1:p.Thr251Ile) [GRCH38: NC_000015.10:g.89330184G>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -
- -
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 251 of the POLG protein (p.Thr251Ile). This variant is present in population databases (rs113994094, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions and in almost all cases it was observed on the same chromosome (in cis) with a second variant, p.Pro587Leu (PMID: 12210792, 15349879, 18546365, 19251978, 19566497, 19578034, 30423451, 30936349, 33396418). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Additionally, the p.Thr251Ile variant has been observed independent from the p.Pro587Leu variant in individual(s) with autosomal recessive POLG-related conditions (PMID: 12707443, 22616202, 23921535). ClinVar contains an entry for this variant (Variation ID: 13503). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLG protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 28154168). For these reasons, this variant has been classified as Pathogenic. -
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:6
This sequence change replaces threonine with isoleucine at codon 251 of the POLG protein (p.Thr251Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (gnomAD 434/282672 heterozygotes, 1 homozygote). The variant has been reported in dbSNP (rs113994094). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 13503). The two POLG variants (c.1760C>T and c.752C>T) detected in this patient have been reported in many individuals affected with POLG-related diseases, and in almost all cases they have been observed on the same chromosome (in cis) (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868) (PS4_moderate). In many of these previously reported cases, the two variants in cis were observed on the opposite chromosome (in trans) from a third, pathogenic variant in an affected individual. The p.Pro587Leu and p.Thr251Ile variant combination in cis accounts for approximately 6% of disease-causing alleles in POLG-related disorders, mainly in Caucasians (PMID: 21880868). The p.Pro587Leu and Thr251Ile variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879) (PP1_moderate). Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; the Thr251Ile+Pro587Leu double variant showed a synergistic effect and had more severe dysfunction than the either of the variants alone (PMID: 28154168) (PS3). -
- -
- -
- -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.154%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013503). The variant was observed in cis with NM_002693.3:c.1760C>T (p.Pro587Leu) in many individuals affected with POLG-related diseases (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
- -
POLG-related disorder Pathogenic:3Other:1
The c.752C>T;p.(Thr251Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant ClinVar ID: 13503; OMIM 174763.0007; PMID: 12210792; 12825077; 15349879; 26224072; 26742794PS4. The p.(Thr251Ile) was detected in trans with a pathogenic variant (PMID: 20385918) - PM3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 25660390) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Variant interpreted as Uncertain significance and reported on 01-29-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
_x000D_Criteria applied: PS3, PS4_SUP, PP1 -
PS3, PM3_Very Strong, PP1 -
Mitochondrial DNA depletion syndrome 4b Pathogenic:2Uncertain:2
This variant was identified as compound heterozygous with NM_001126131.2:c.1760C>T. -
- -
A heterozygous missense variation in exon 3 of the POLG gene that results in the amino acid substitution of Isoleucine for Threonine at codon251 was detected. The observed variant c.752C>T (p.Thr251lle) has a minor allele frequancy of 0.08% and 0.1% in the 1000 genomes and gnomAD databases respectively. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
ACMG classification criteria: PS3 supporting, PS4 strong, PS4, PM3 strong -
Mitochondrial disease Pathogenic:1Other:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial disease (MONDO#0044970), POLG-related. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 608 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the exonuclease domain (PMID: 28154168). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is often seen in cis with p.(Pro587Leu), and this haplotype has been reported as homozygous or compound heterozygous with a third variant in affected individuals (ClinVar, GeneReviews, PMID: 25660390, 15349879). While rare, p.(Pro587Leu) and p.(Thr251Ile) in cis without a third variant have been reported in homozygous individuals and primarily associated with late-onset disease (VCGS cohort; PMIDs: 15349879, 19251978, 27538604, 25660390); however, some early-onset disease has also been reported (PMIDs: 21138766, 29474836). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies show that this variant reduces thermostability and impairs catalytic activity. The dysfunction is more severe when the variant is in cis with p.(Pro587Leu) (PMID: 28154168). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
- -
POLG-Related Spectrum Disorders Pathogenic:1
- -
Inborn genetic diseases Pathogenic:1
The c.752C>T (p.T251I) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 752, causing the threonine (T) at amino acid position 251 to be replaced by an isoleucine (I). Based on the available evidence, the c.752C>T (p.T251I) alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant progressive external ophthalmoplegia. Based on data from gnomAD, the T allele has an overall frequency of 0.154% (434/282672) total alleles studied. The highest observed frequency was 0.267% (344/129038) of European (non-Finnish) alleles. This mutation has been reported to occur almost exclusively in cis with p.P587L (c.1760C>T) and this syntenic mutation combination accounts for approximately 6% of all disease causing alleles in POLG (Tang, 2011). This syntenic mutation combination has been detected alone, in trans with various other POLG mutations and alterations, and as homozygous, in individuals with Alpers syndrome, possible Kearns-Sayre syndrome, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability, and various other POLG-deficiency symptoms (Dames, 2013; Van Goethem, 2003; Blok, 2009; Uusimaa, 2013; Weiss, 2010; Horvath, 2006; Tang, 2011). Of note, this mutation has been detected without p.P587L (c.1760C>T) in an individual with Parkinson disease without another POLG alteration and in another individual who also carried POLG p.G848S (phase was not confirmed) with sensory ataxic neuropathy, dysarthria/dysphagia, and external ophthalmoplegia (SANDO) (Gáti, 2011; Gui, 2015). This amino acid position is not well conserved in available vertebrate species. Biochemical characterization of T251I mutant revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity; T251I+P587L double mutant showed synergistic effect and had more severe dysfunction than T251I alone (DeBalsi, 2017). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:1
- -
Hereditary spastic paraplegia Pathogenic:1
- -
Hypertrophic cardiomyopathy Pathogenic:1
The variant was classified as pathogenic according to the ACMG Guidelines, 2015. The variant was found with an allele frequency of 0.1535% (one reported homozygote) in the control populations from the gnomAD v2.1.1 project. The variant has conflicting predictions of pathogenicity, based on in silico data analysis (Polyphen-2 and SIFT - benign, Mutation-Taster - disease causing), with the position being poorly conserved and threonine and isoleucine having moderate physicochemical difference. The variant was identified in cis with variant POLG(NM_002693.3):c.1760C>T in a patient with Hypertrophic cardiomyopathy. The patient is also carrier of variants GTPBP3(NM_032620.4):c.181G>C and GTPBP3(NM_032620.4):c.1199C>T in compound heterozygous state. -
Global developmental delay Pathogenic:1
- -
not specified Pathogenic:1
- -
Abnormality of the nervous system Pathogenic:1
- -
Mitochondrial DNA depletion syndrome 1 Pathogenic:1
- -
Tip-toe gait Pathogenic:1
The variant c.752C> T p. (Thr251Ile) [dbSNP: rs113994094, frequency: A = 0.15%, GnomAD] is rated by the majority (15 entries) as "probably pathogenic" and "pathogenic" in the ClinVar mutation database. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -
Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1
- -
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 Pathogenic:1
- -
See cases Uncertain:1
ACMG categories: PM1,PM2,PP3,BP1 -
Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Other:1
Variant classified as Pathogenic and reported on 04-20-2016 by Children's National Medical Center. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at