The NM_002693.2:c.3509T>G (NP_002684.1:p.Leu1170Arg) [GRCH38: NC_000015.10:g.89317510A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.3509T>G (p.Leu1170Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(4)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(3)
Likely pathogenic(1); Uncertain significance(3)
4
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.3509T>G (p.Leu1170Arg)
Variation ID: 206618 Accession: VCV000206618.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89317510 (GRCh38) [ NCBI UCSC ] 15: 89860741 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 11, 2019 Nov 24, 2024 Oct 13, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002693.3:c.3509T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Leu1170Arg missense NM_001126131.2:c.3509T>G NP_001119603.1:p.Leu1170Arg missense NC_000015.10:g.89317510A>C NC_000015.9:g.89860741A>C NG_008218.2:g.22286T>G NG_011736.1:g.78548A>C LRG_500:g.78548A>C LRG_765:g.22286T>G LRG_765t1:c.3509T>G LRG_765p1:p.Leu1170Arg - Protein change
- L1170R
- Other names
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- Canonical SPDI
- NC_000015.10:89317509:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| POLG | - | - |
GRCh38 GRCh37 |
1883 | 3025 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Oct 13, 2022 | RCV000758327.12 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Oct 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
|
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000886991.1
First in ClinVar: Mar 11, 2019 Last updated: Mar 11, 2019 |
Comment:
The NM_002693.2:c.3509T>G (NP_002684.1:p.Leu1170Arg) [GRCH38: NC_000015.10:g.89317510A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets … (more)
The NM_002693.2:c.3509T>G (NP_002684.1:p.Leu1170Arg) [GRCH38: NC_000015.10:g.89317510A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic. (less)
|
|
|
Uncertain significance
(Oct 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001226732.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1170 of the POLG protein (p.Leu1170Arg). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1170 of the POLG protein (p.Leu1170Arg). This variant is present in population databases (rs796052913, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206618). 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. 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. (less)
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Uncertain significance
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573355.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.87). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormality of metabolism/homeostasis (present)
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Uncertain significance
(May 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399214.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
A heterozygous missense variant was identified, NM_002693.2(POLG):c.3509T>G in exon 22 of the POLG gene. This substitution is predicted to create a major amino acid change … (more)
A heterozygous missense variant was identified, NM_002693.2(POLG):c.3509T>G in exon 22 of the POLG gene. This substitution is predicted to create a major amino acid change from a leucine to an arginine at position 1170 of the protein; NP_002684.1(POLG):p.(Leu1170Arg). The leucine at this position has high conservation (100 vertebrates, UCSC), and is located within the DNA polymerase family A domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, FATHMM, PROVEAN). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). This variant has been reported once as likely pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
|
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1170 of the POLG protein (p.Leu1170Arg). This variant is present in population databases (rs796052913, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206618). 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. 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.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.87). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Comment:
A heterozygous missense variant was identified, NM_002693.2(POLG):c.3509T>G in exon 22 of the POLG gene. This substitution is predicted to create a major amino acid change from a leucine to an arginine at position 1170 of the protein; NP_002684.1(POLG):p.(Leu1170Arg). The leucine at this position has high conservation (100 vertebrates, UCSC), and is located within the DNA polymerase family A domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, FATHMM, PROVEAN). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). This variant has been reported once as likely pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The NM_002693.2:c.3509T>G (NP_002684.1:p.Leu1170Arg) [GRCH38: NC_000015.10:g.89317510A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1170 of the POLG protein (p.Leu1170Arg). This variant is present in population databases (rs796052913, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206618). 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. 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.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.87). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Comment:
A heterozygous missense variant was identified, NM_002693.2(POLG):c.3509T>G in exon 22 of the POLG gene. This substitution is predicted to create a major amino acid change from a leucine to an arginine at position 1170 of the protein; NP_002684.1(POLG):p.(Leu1170Arg). The leucine at this position has high conservation (100 vertebrates, UCSC), and is located within the DNA polymerase family A domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, FATHMM, PROVEAN). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). This variant has been reported once as likely pathogenic (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs796052913 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.