ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.3527C>T (p.Ser1176Leu)
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.
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.
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.3527C>T (p.Ser1176Leu)
Variation ID: 430382 Accession: VCV000430382.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89317492 (GRCh38) [ NCBI UCSC ] 15: 89860723 (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 Jul 2, 2017 May 1, 2024 Dec 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002693.3:c.3527C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Ser1176Leu missense NM_001126131.2:c.3527C>T NP_001119603.1:p.Ser1176Leu missense NC_000015.10:g.89317492G>A NC_000015.9:g.89860723G>A NG_008218.2:g.22304C>T NG_011736.1:g.78530G>A LRG_500:g.78530G>A LRG_765:g.22304C>T LRG_765t1:c.3527C>T LRG_765p1:p.Ser1176Leu - Protein change
- S1176L
- Other names
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- Canonical SPDI
- NC_000015.10:89317491:G:A
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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 |
1 | 2962 | |
POLGARF | - | - | GRCh38 | - | 2918 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 29, 2021 | RCV000493365.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 8, 2021 | RCV001375606.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2023 | RCV000686358.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2022 | RCV002524050.2 |
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
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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
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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
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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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Uncertain significance
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: no
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251868.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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POLG-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001572514.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
Variant summary: POLG c.3527C>T (p.Ser1176Leu) results in a non-conservative amino acid change located in the palm domain (IPR001098) of the encoded protein sequence. Five of … (more)
Variant summary: POLG c.3527C>T (p.Ser1176Leu) results in a non-conservative amino acid change located in the palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251486 control chromosomes (gnomAD). The variant, c.3527C>T, has been reported in the literature in a single family, with four compound heterozygous individuals affected with autosomal recessive progressive external ophthalmoplegia (Lamantea_2002, Lamantea_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jan 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000583174.3
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12210792, 15913923, 15349879, 32347949) (less)
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Pathogenic
(Dec 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000813874.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1176 of the POLG protein (p.Ser1176Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1176 of the POLG protein (p.Ser1176Leu). This variant is present in population databases (rs776031396, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 12210792, 15349879). 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. ClinVar contains an entry for this variant (Variation ID: 430382). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205863.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Feb 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003751618.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.3527C>T (p.S1176L) alteration is located in exon 22 (coding exon 21) of the POLG gene. This alteration results from a C to T substitution … (more)
The c.3527C>T (p.S1176L) alteration is located in exon 22 (coding exon 21) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 3527, causing the serine (S) at amino acid position 1176 to be replaced by a leucine (L). Based on the available evidence, this variant is expected to be causative of autosomal recessive POLG-related mitochondrial disorders when present along with a second pathogenic or likely pathogenic variant on the other allele; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is unclear. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (2/251486) total alleles studied. The highest observed frequency was <0.01% (2/113762) of European (non-Finnish) alleles. The p.S1176L variant was detected in trans with a second POLG variant and co-segregated with disease in one family with autosomal recessive progressive external ophthalmoplegia (Lamantea, 2002; Lamantea, 2004). 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 likely pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Assessment of Interlaboratory Variation in the Interpretation of Genomic Test Results in Patients With Epilepsy. | SoRelle JA | JAMA network open | 2020 | PMID: 32347949 |
Pathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database. | Nurminen A | BBA clinical | 2017 | PMID: 28480171 |
Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes. | Farnum GA | Biochimica et biophysica acta | 2014 | PMID: 24508722 |
Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene. | Lamantea E | Annals of neurology | 2004 | PMID: 15349879 |
Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. | Lamantea E | Annals of neurology | 2002 | PMID: 12210792 |
Text-mined citations for rs776031396 ...
HelpRecord last updated May 01, 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.