VCV000252958.10 - ClinVar

NM_007215.4(POLG2):c.544C>T (p.Arg182Trp)

Germline

Classification

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.

(5)

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(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007215.4(POLG2):c.544C>T (p.Arg182Trp)

Variation ID: 252958 Accession: VCV000252958.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q23.3 17: 64496425 (GRCh38) [ NCBI UCSC ] 17: 62492543 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 26, 2016	Feb 14, 2024	Jun 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_007215.4:c.544C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009146.2:p.Arg182Trp	missense
NC_000017.11:g.64496425G>A
NC_000017.10:g.62492543G>A
NG_013029.1:g.5642C>T

Protein change

R182W

Other names

Canonical SPDI

NC_000017.11:64496424:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA10586136 OMIM: 604983.0006 dbSNP: rs886037843 VarSome

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
Gene	OMIM	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.
MILR1	-	-	-	GRCh38 GRCh37	-	458
POLG2		-	-	GRCh38 GRCh37	6	463

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.
Acute liver failure	Likely pathogenic (1)	criteria provided, single submitter	Jun 1, 2016	RCV000258005.3
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jun 19, 2023	RCV000432548.6
Mitochondrial DNA depletion syndrome 16A	Pathogenic (1)	no assertion criteria provided	Jul 15, 2021	RCV000824678.4
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	Uncertain significance (1)	no assertion criteria provided	Nov 2, 2021	RCV002290967.3

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.
Likely pathogenic (Jun 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acute liver failure (Autosomal recessive inheritance) Affected status: no, yes Allele origin: germline, unknown	Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center Accession: SCV000297744.1 First in ClinVar: Oct 26, 2016 Last updated: Oct 26, 2016	Publications: PubMed (1) PubMed: 27592148 Comment: Parents are heterozygous and phenotypically normal. The patient is homozygous and has severe mtDNA depeletion. POLG2 encodes the accessory subunit of DNA polymerase and is … (more) Parents are heterozygous and phenotypically normal. The patient is homozygous and has severe mtDNA depeletion. POLG2 encodes the accessory subunit of DNA polymerase and is involved in mtDNA replication. (less) Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 2
Likely pathogenic (Aug 02, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000530691.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: The R182W variant in the POLG2 gene has been reported in the homozygous state in an individual with infantile fulminant liver failure and mitochondrial depletion … (more) The R182W variant in the POLG2 gene has been reported in the homozygous state in an individual with infantile fulminant liver failure and mitochondrial depletion in liver and muscle. This individual's heterozygous parents were reportedly unaffected (Varma et al., 2016). The R182W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R182W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R182W as a likely pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
Uncertain significance (Jun 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003442508.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 30157269‚ 27592148 Comment: 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 … (more) 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects POLG2 function (PMID: 30157269). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 252958). This missense change has been observed in individual(s) with POLG2-related conditions (PMID: 27592148). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 182 of the POLG2 protein (p.Arg182Trp). (less)
Pathogenic (Jul 15, 2021)	no assertion criteria provided Method: literature only	MITOCHONDRIAL DNA DEPLETION SYNDROME 16A (HEPATIC TYPE) (1 patient) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000965602.2 First in ClinVar: Aug 14, 2019 Last updated: Jul 18, 2021	Publications: PubMed (2) PubMed: 27592148‚ 30157269 Comment on evidence: In a male infant with mitochondrial DNA depletion syndrome-16A (MTDPS16A; 618528) resulting in fulminant liver failure and death in infancy, Varma et al. (2016) identified … (more) In a male infant with mitochondrial DNA depletion syndrome-16A (MTDPS16A; 618528) resulting in fulminant liver failure and death in infancy, Varma et al. (2016) identified a homozygous c.544C-T transition (c.544C-T, 007215.3) in the POLG2 gene, resulting in an arg182-to-trp (R182W) substitution at a residue in the dimerization base that is conserved in vertebrates. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in the heterozygous state in each unaffected parent, confirming segregation. The variant was not found in the 1000 Genomes Project, Exome Variant Server, and ExAC databases. Functional studies of the variant were not performed, but the variant was predicted to disrupt POLG2 homodimerization and cause loss of progressive mtDNA synthesis. Patient tissues showed variable degrees of mtDNA depletion. Hoff et al. (2018) performed functional studies on the R182W variant. Patient-derived fibroblasts showed a growth defect associated with reduced mtDNA copy number and decreased mRNA levels of both POLG (174763) and POLG2 compared to controls. HEK293 cells transfected with the mutation showed defective oxidative phosphorylation, impaired respiratory activity, and decreased ATP production. The R182W protein showed similar DNA-binding abilities and association with POLG as wildtype POLG2. However, the mutant protein showed reduced thermostability, suggesting structural instability, and impaired ability to stimulate POLG compared to wildtype. (less)
Uncertain significance (Nov 02, 2021)	no assertion criteria provided Method: clinical testing	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002583325.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022

Comment:

The R182W variant in the POLG2 gene has been reported in the homozygous state in an individual with infantile fulminant liver failure and mitochondrial depletion in liver and muscle. This individual's heterozygous parents were reportedly unaffected (Varma et al., 2016). The R182W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R182W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R182W as a likely pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

Comment:

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects POLG2 function (PMID: 30157269). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 252958). This missense change has been observed in individual(s) with POLG2-related conditions (PMID: 27592148). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 182 of the POLG2 protein (p.Arg182Trp).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome.	Hoff KE	PloS one	2018	PMID: 30157269
Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion.	Varma H	European journal of medical genetics	2016	PMID: 27592148

Text-mined citations for rs886037843 ...

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 29, 2024

ClinVar Genomic variation as it relates to human health

NM_007215.4(POLG2):c.544C>T (p.Arg182Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886037843 ...