NM_002693.3:c.2243G>C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBP4
The NM_002693.3(POLG):c.2243G>C(p.Trp748Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,612,926 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 Likely pathogenic (★★).
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000742 AC: 113AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000971 AC: 244AN: 251290Hom.: 0 AF XY: 0.000987 AC XY: 134AN XY: 135828
GnomAD4 exome AF: 0.000730 AC: 1066AN: 1460716Hom.: 1 Cov.: 31 AF XY: 0.000736 AC XY: 535AN XY: 726750
GnomAD4 genome 0.000742 AC: 113AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.00108 AC XY: 80AN XY: 74364
ClinVar
Submissions by phenotype
not provided Pathogenic:13Other:1
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In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447) -
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POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
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Progressive sclerosing poliodystrophy Pathogenic:8
The NM_002693.2:c.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . 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. 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. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), 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 disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4 -
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Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:6
This variant is interpreted as Pathogenic for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE). The following ACMG Tag(s) were applied: PM2 =>Absent from controls (or at extremely low frequency if recessive) in gnomAD. PM3_very strong => For recessive disorders, detected in trans with a pathogenic variant (PMID: 15477547; 15929042; 15824347; 18828154; 19578034). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-moderate => Well-established functional studies show a deleterious effect (PMID:17088268). -
Criteria applied: PS3,PM3_STR,PS4_MOD,PP3 -
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The missense c.2243G>C (p.Trp748Ser) in the POLG gene has been observed in individual(s) with autosomal recessive POLG-related disease (Chan, Sherine S L et al.,2006). It is commonly reported in individuals of Finnish ancestry. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). This variant is reported with the allele frequency (0.09%) in the gnomAD Exomes. It is submitted to ClinVar as uncertain Significance/ Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence predicts a damaging effect on protein structure and function for this variant (Polyphen – score1.00; Sift – score 0.01; Mutation Taster – score 1.00). The amino acid Trptophan at position 748 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp748Ser in POLG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
POLG-Related Spectrum Disorders Pathogenic:3
The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3. -
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Variant summary: POLG c.2243G>C (p.Trp748Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251290 control chromosomes. c.2243G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders as both homozygote and compound heterozygote genotypes (e.g. Tzoulis_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Chan_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17088268, 16638794). 29 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=25), likely pathogenic (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Mitochondrial disease Pathogenic:2Other:1
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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 POLG-related mitochondrial disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants are usually inherited in a recessive manner, however progressive external ophthalmoplegia can also be dominant when heterozygous variants are located in the highly conserved active site of motif B of the polymerase domain (PMID: 30451971). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 30423451). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 280 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with autosomal recessive with POLG-related mitochondrial disorder. In addition, it has been reported in affected and unaffected carriers, which could be due to variable expressivity or potentially missed second variant (ClinVar, PMID: 30423451, PMID: 34288125). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Mitochondrial DNA depletion syndrome 4b Pathogenic:2
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4. -
not specified Pathogenic:1
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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.2243G>C (p.W748S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2243, causing the tryptophan (W) at amino acid position 748 to be replaced by a serine (S). Based on the available evidence, this alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.099% (280/282688) total alleles studied. The highest observed frequency was 0.621% (156/25104) of European (Finnish) alleles. The c.2243G>C (p.W748S) alteration accounts for approximately 8% of disease causing alleles in the Finnish population. This alteration has been identified in the homozygous state and in conjunction with another alteration in POLG in multiple individuals with Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, dysarthria/dysphagia, and external ophthalmoplegia (SANDO), and other autosomal recessive POLG-related mitochondrial disorders (Bychkov, 2021; Masingue, 2019; Henao, 2016; Hakonen, 2007; Janssen, 2016; Uusimaa, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
POLG-related disorder Pathogenic:1
The POLG c.2243G>C variant is predicted to result in the amino acid substitution p.Trp748Ser. This variant has been documented as pathogenic for autosomal recessive POLG-related disorders (Tang et al. 2011. PubMed ID: 21880868). It is a common founder variant for autosomal recessive progressive ataxia in the Finnish population (Hakonen et al. 2005. PubMed ID: 16080118). This variant is reported in 0.62% of alleles in individuals of European (Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic. -
Spinocerebellar ataxia with epilepsy Pathogenic:1
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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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at