rs113994096
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4
The NM_002693.3(POLG):c.1760C>T(p.Pro587Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,612,514 control chromosomes in the GnomAD database, including 2 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
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00152 AC: 232AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00155 AC: 386AN: 249778Hom.: 1 AF XY: 0.00158 AC XY: 214AN XY: 135208
GnomAD4 exome AF: 0.00203 AC: 2969AN: 1460200Hom.: 2 Cov.: 33 AF XY: 0.00197 AC XY: 1433AN XY: 726516
GnomAD4 genome 0.00152 AC: 232AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107AN XY: 74476
ClinVar
Submissions by phenotype
not provided Pathogenic:15Uncertain:1
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This variant is seen in cis with POLG c.752C>T (p.Thr251Ile), and the pathogenicity assessment is based on data for NM_002693.2:c.752C>T(;)1760C>T. -
POLG: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
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PP3, PM2, PS3_moderate -
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Progressive sclerosing poliodystrophy Pathogenic:6Uncertain:2
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The NM_002693.2:c.1760C>T (NP_002684.1:p.Pro587Leu) [GRCH38: NC_000015.10:g.89325639G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 ; 12825077 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
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The missense variant p.Pro587Leu has been previously reported in multiple studies with p.Thr251Ile 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 sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (rs113994096, 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 (p.Thr251Ile) variant (PMID: 12210792, 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). 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. To date, the p.Pro587Leu variant has been observed independent from the p.Thr251Ile variant in one individual with autosomal recessive POLG-related conditions (PMID: 16401742). ClinVar contains an entry for this variant (Variation ID: 13505). 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 expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 28154168). In summary, this is a rare variant that is almost always observed in cis with a second variant. It has been shown to segregate with disease, and has also been observed in many individuals with sporadic disease. However, because it almost always occurs in cis with p.Thr251Ile, the individual contribution of this variant to disease cannot be disambiguated. For these reasons, this change has been classified as a Variant of Uncertain Significance. -
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POLG-related disorder Pathogenic:5
The POLG c.1760C>T p.(Pro587Leu) missense variant is well described in the literature and has been reported in individuals with a phenotype consistent with POLG-related spectrum disorders (Van Goethem et al., 2003; Filosto et al. 2003; Lamantea et al. 2004; Wong et al., 2008; Ashley et al., 2008; Burusnukul et al. 2009; Weiss et al. 2010; Tang et al. 2011; Horvath et al., 2006; Dames et al. 2013; Helbling et al. 2013; Uusimaa et al. 2013). In almost all of the reported cases, the p.Pro587Leu variant was found in cis with p.Thr251Ile as the complex allele [p.Thr251Ile; p.Pro587Leu]. In an additional two individuals, the p.Pro587Leu variant was found as part of a complex allele with a p.Pro589Leu variant. The p.Pro587Leu variant has also been reported independently in three individuals from the same family in a heterozygous state displaying a dominant pattern of inheritance. Euro et al. (2011) assessed the structure-function relationships of variants in the POLG gene and reported that the p.Pro587Leu variant constrains the Beta-hairpin loop between the IP and AID subdomains and postulate it likely reduces processivity as a result of misalignment of the ptDNA with respect to the catalytic site. DeBalsi et al. (2017) investigated the biochemical properties of purified recombinant Pol gamma p.Pro587Leu protein expressed using the baculovirus Sf9 system. Experiments demonstrated that the p.Pro587Leu variant caused a two-fold reduction in DNA binding affinity and significantly reduced thermostability. The catalytic efficiency of the p.Pro587Leu protein was reduced to approximately 32% of the wildtype level. The [p.Thr251Ile; p.Pro587Leu] variant protein demonstrated a more severe catalytic dysfunction, retaining 5% activity compared to the wild type protein and suggesting that these two variants have a synergistic effect. Based on the collective evidence the p.Pro587Leu variant is classified as pathogenic when found as part of a complex allele and of uncertain significance when found independently. -
The patient has compund heterozygous variant; the other variant is POLG: c.752C>T. These variants may affect the function of the DNA polymerase gamma, which is essential for mitochondrial DNA replication and maintenance. The patient presented with clinical features consistent with POLG-related disorders. Given the presence of compound heterozygosity, these variants should be assessed under ACMG/AMP guidelines, considering PM3 (for trans configuration), PP3 (in silico predictions), and any available functional evidence. Further segregation analysis and biochemical studies may help determine their pathogenicity. -
PS3, PM3_Strong, PP1, PP3 -
_x000D_Criteria applied: PS3, PS4_SUP, PP3, PP1 -
The c.1760C>T;p.(Pro587Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13505; OMIM 174763.0011; PMID: 12825077; 25660390; 12975295; 1539879; 19578034; 24265579; 23448099;25742477; 26224072) - PS4.The p.(Pro587Leu) was detected in trans with a pathogenic variant (PMID: 19578034) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. 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. -
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:4
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Mitochondrial DNA depletion syndrome 4b Pathogenic:3Uncertain:1
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A heterozygous missense variation in exon 10 of the POLG gene that results in the amino acid substitution of Leucine for Proline at codon587 was detected. The observed variant c.1760C>T (p.Pro587Leu) has a minor allele frequancy of 0.08% and 0.1% in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging 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 likely pathogenic. -
The POLG c.1760C>T variant is classified as LIKELY PATHOGENIC (PS3, PS4_moderate, PP1_moderate, PP3) This sequence change in exon 10 of 23 replaces proline with leucine at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (gnomAD 232/152196 heterozygotes, 0 homozygote). The variant has been reported in dbSNP (rs113994096). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 13505). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it has been observed on the same chromosome (in cis) with the second (p.Thr251Ile) variant also detected in this patient (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). NO THIRD POLG variant was detected in this patient -
Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015) -
Mitochondrial disease Pathogenic:2Other: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 proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 606 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the linker region (PMID: 28154168). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is often seen in cis with p.(Thr251Ile), 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.(Thr251Ile) (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 -
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Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:2
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.50 (damaging >=0.6, benign <0.4), 3Cnet: 0.45 (damaging >=0.6, benign <0.15)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181617 /PMID: 19466586 /3billion dataset). A different missense change at the same codon (p.Arg151Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012414 /PMID: 11684629). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
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Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:2
ACMG classification criteria: PS3 supporting, PS4 strong, PS4, PM3 strong, PP3 supporting -
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Inborn genetic diseases Pathogenic:1
The c.1760C>T (p.P587L) alteration is located in exon 10 (coding exon 9) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 1760, causing the proline (P) at amino acid position 587 to be replaced by a leucine (L). Based on the available evidence, the c.1760C>T (p.P587L) 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% (433/281158) total alleles studied. The highest observed frequency was 0.265% (341/128840) of European (non-Finnish) alleles. This mutation has been reported to occur almost exclusively in cis with p.T251I (c.752C>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, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability, and various other POLG-deficiency symptoms (Van Goethem, 2003; Uusimaa, 2013; Weiss, 2010; Horvath, 2006; Tang, 2011). Of note, this mutation has been detected without p.T251I in conjunction with the p.R853W alteration (phase was not confirmed) in an individual with PEO, ptosis, and multiple mtDNA deletions (González-Vioque, 2006). This amino acid position is highly conserved in available vertebrate species. Biochemical characterization of P587L 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 P587L alone (DeBalsi, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Hereditary spastic paraplegia Pathogenic:1
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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 0.1540% (one reported homozygote) in the control populations from the gnomAD v2.1.1 project. In silico analysis by Polyphen-2, SIFT and Mutation-Taster predicted it as damaging. The amino acid change is in a highly conserved position and proline and leucine have moderate physicochemical difference. The variant was identified in cis with variant POLG(NM_002693.3):c.752C>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. -
not specified Pathogenic:1
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Global developmental delay Pathogenic:1
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Abnormality of the nervous system Pathogenic:1
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Mitochondrial DNA depletion syndrome 1 Pathogenic:1
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Tip-toe gait Pathogenic:1
c.1760C>T p.(Pro587Leu) [dbSNP: rs113994096, Frequenz: 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. -
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