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NM_002693.2(POLG):c.3667A>G (p.Ile1223Val)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Sep 2, 2021)
Last evaluated:
Aug 20, 2020
Accession:
VCV000458718.6
Variation ID:
458718
Description:
single nucleotide variant
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NM_002693.2(POLG):c.3667A>G (p.Ile1223Val)

Allele ID
464568
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q26.1
Genomic location
15: 89316804 (GRCh38) GRCh38 UCSC
15: 89860035 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_500t1:c.*345T>C
LRG_765:g.22992A>G
NC_000015.10:g.89316804T>C
... more HGVS
Protein change
I1223V
Other names
-
Canonical SPDI
NC_000015.10:89316803:T:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00003
Links
ClinGen: CA7724040
dbSNP: rs148786642
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Oct 31, 2018 RCV000765232.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Aug 20, 2020 RCV000548544.5
Uncertain significance 1 no assertion criteria provided May 24, 2021 RCV001591204.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
FANCI - - GRCh38
GRCh37
576 683
POLG - - GRCh38
GRCh37
1276 1392

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(Oct 01, 2018)
criteria provided, single submitter
Method: clinical testing
Progressive sclerosing poliodystrophy
Allele origin: germline
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000887304.1
Submitted: (Nov 16, 2018)
Evidence details
Comment:
The NM_002693.2:c.3667A>G (NP_002684.1:p.Ile1223Val) [GRCH38: NC_000015.10:g.89316804T>C] variant in FANCI gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets … (more)
Uncertain significance
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1
Progressive sclerosing poliodystrophy
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Mitochondrial DNA depletion syndrome 1 (MNGIE type)
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Mitochondrial DNA depletion syndrome 4B, MNGIE type
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000896468.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Uncertain significance
(Aug 20, 2020)
criteria provided, single submitter
Method: clinical testing
Progressive sclerosing poliodystrophy
Allele origin: germline
Invitae
Accession: SCV000630157.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (1)
Comment:
This sequence change replaces isoleucine with valine at codon 1223 of the POLG protein (p.Ile1223Val). The isoleucine residue is moderately conserved and there is a … (more)
Uncertain significance
(May 24, 2021)
no assertion criteria provided
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001822624.1
Submitted: (Sep 02, 2021)
Evidence details
Comment:
Reported in the heterozygous state in an individual with a clinical presentation suggestive of POLG deficiency; however, information regarding parental testing was not available (Tang … (more)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. Tang S Journal of medical genetics 2011 PMID: 21880868

Text-mined citations for rs148786642...

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These 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 Sep 07, 2021