ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.1270_1271del (p.Leu424fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.1270_1271del (p.Leu424fs)
Variation ID: 206608 Accession: VCV000206608.13
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 15q26.1 15: 89327329-89327330 (GRCh38) [ NCBI UCSC ] 15: 89870560-89870561 (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 Oct 9, 2016 Feb 14, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002693.3:c.1270_1271del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Leu424fs frameshift NM_001126131.2:c.1270_1271del NP_001119603.1:p.Leu424fs frameshift NM_002693.2:c.1270_1271delCT NC_000015.10:g.89327329AG[1] NC_000015.9:g.89870560AG[1] NG_008218.2:g.12464CT[1] LRG_765:g.12464CT[1] - Protein change
- L424fs
- Other names
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- Canonical SPDI
- NC_000015.10:89327328:AGAG:AG
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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.
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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
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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 | 2960 | |
POLGARF | - | - | - | GRCh38 | - | 2916 |
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
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
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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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2021 | RCV000188674.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2016 | RCV000449589.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000758260.9 |
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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Pathogenic
(Nov 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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None
Generalized epilepsy Obesity
Affected status: yes
Allele origin:
paternal
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Claritas Genomics
Accession: SCV000537855.1
First in ClinVar: Mar 27, 2017 Last updated: Mar 27, 2017 |
Comment:
The c.1270_1271delCT (p.Leu424Glyfs*29) missense variant in the POLG gene is previously reported in the literature and is expected to be causative of disease, typically as … (more)
The c.1270_1271delCT (p.Leu424Glyfs*29) missense variant in the POLG gene is previously reported in the literature and is expected to be causative of disease, typically as a recessive disorder. Homozygous or compound heterozygous pathogenic variants in this gene are associated with a range of mitochondrial conditions including, Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy syndrome (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), mitochondrial DNA depletion syndrome 4B (MNGIE type), mitochondrial ataxia neuropathy spectrum (includes SANDO and SCAE) and progressive external ophthalmoplegia. Progressive external ophthalmoplegia can also be inherited in an autosomal dominant manner. These conditions are known to have variable expressivity, including a wide range in age of onset as well as reduced penetrance. This deletion of two basepairs results in a shift in the reading frame at position p.Leu424 and introduces a premature stop codon 28 positions downstream, which is predicted to result in protein truncation or nonsense mediated decay. It has been reported in the compound heterozygous state in one individual with adult-onset progressive external ophthalmoplegia and one child with Alpers syndrome. It has not been observed in the 1000 Genomes, ExAC, or NHLBI Exome Sequencing Project control databases. Therefore, due to the predicted loss-of-function effect of the variant and prior reports in the literature, it is classified as pathogenic. (less)
Sex: male
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Pathogenic
(Oct 01, 2018)
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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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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000886900.1
First in ClinVar: Mar 11, 2019 Last updated: Mar 11, 2019 |
Comment:
The NM_002693.2:c.1270_1271del (NP_002684.1:p.Leu424GlyfsTer29) [GRCH38: NC_000015.10:g.89327331_89327332del] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been … (more)
The NM_002693.2:c.1270_1271del (NP_002684.1:p.Leu424GlyfsTer29) [GRCH38: NC_000015.10:g.89327331_89327332del] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12707443 . This variant meets the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predicted null variant in POLG where loss of function is a known mechanism of disease. 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. PM4:This variant causes alteration in the length of expressed protein. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. (less)
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Pathogenic
(Apr 05, 2017)
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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: SCV000242298.11
First in ClinVar: Aug 07, 2015 Last updated: Oct 09, 2016 |
Comment:
c.1270_1271delCT: p.Leu424GlyfsX29 (L424Gfsx29) in exon 7 of the POLG gene (NM_002693.2). The normal sequence with the bases that are deleted in braces is: GACT{CT}GGCC.The c.1270_1271delCT … (more)
c.1270_1271delCT: p.Leu424GlyfsX29 (L424Gfsx29) in exon 7 of the POLG gene (NM_002693.2). The normal sequence with the bases that are deleted in braces is: GACT{CT}GGCC.The c.1270_1271delCT mutation in the POLG gene has been reported in a child with Alpers syndrome and in an individual with adult-onset progressive external ophthalmoplegia (PEO) and multiple mtDNA deletions, both of whom had a second identified mutation in the POLG gene (Wong et al., 2008; Agostino et al., 2003). The deletion causes a frameshift starting with codon Leucine 424, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Leu424GlyfsX29. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in INFANT-EPI panel(s). (less)
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Pathogenic
(Jun 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001879826.2
First in ClinVar: Sep 19, 2021 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in trans with a pathogenic POLG variant in at least one individual with clinical features associated with this gene. (less)
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Pathogenic
(Dec 19, 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: SCV001220597.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu424Glyfs*29) in the POLG gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu424Glyfs*29) in the POLG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365). This variant is present in population databases (rs796052908, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 12707443, 18546365). ClinVar contains an entry for this variant (Variation ID: 206608). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 14, 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: SCV004205877.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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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
HelpText-mined citations for rs796052908 ...
HelpRecord last updated Feb 20, 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.