NM_002693.3(POLG):c.2554C>T (p.Arg852Cys) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Aug 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000188581.33

Allele description [Variation Report for NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)]

NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)

Genes:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
POLGARF:POLG alternative reading frame [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)

Other names:

p.R852C:CGC>TGC

HGVS:

NC_000015.10:g.89321780G>A
NG_008218.2:g.18016C>T
NM_001126131.2:c.2554C>T
NM_002693.3:c.2554C>TMANE SELECT
NP_001119603.1:p.Arg852Cys
NP_002684.1:p.Arg852Cys
NP_002684.1:p.Arg852Cys
LRG_765t1:c.2554C>T
LRG_765:g.18016C>T
LRG_765p1:p.Arg852Cys
NC_000015.9:g.89865011G>A
NM_002693.2:c.2554C>T

Protein change:

R852C

Links:

dbSNP: rs144500145

NCBI 1000 Genomes Browser:

rs144500145

Molecular consequence:

NM_001126131.2:c.2554C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.2554C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000242203	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 20, 2022)	germline	clinical testing	Citation Link,
SCV000610294	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001145154	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Mar 2, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 30167885, 29474836, 16545482, 17426723, 18546365, 19251978, 19478085, 32445240, 20818383, 34052969, 19862739, 21259344, 21484424, 22494076, 23084792, 31085725, 32964447, 22000311, 21880868, 26467025
SCV001149562	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2023)	germline	clinical testing	Citation Link,
SCV001808637	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001971371	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

Papandreou A, Rahman S, Fratter C, Ng J, Meyer E, Carr LJ, Champion M, Clarke A, Gissen P, Hemingway C, Hussain N, Jayawant S, King MD, Lynch BJ, Mewasingh L, Patel J, Prabhakar P, Neergheen V, Pope S, Heales SJR, Poulton J, Kurian MA.

J Inherit Metab Dis. 2018 Nov;41(6):1275-1283. doi: 10.1007/s10545-018-0227-7. Epub 2018 Aug 30. Erratum in: J Inherit Metab Dis. 2018 Nov;41(6):1299-1301. doi: 10.1007/s10545-018-0247-3.

PubMed [citation]

PMID:: 30167885
PMCID:: PMC6326959

See all PubMed Citations (21)

Details of each submission

From GeneDx, SCV000242203.15

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies of R852C demonstrate polymerase assays retained less than 1% that of wildtype polymerase activity, demonstrating a damaging effect (Kasiviswanathan et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20818383, 23545419, 17426723, 24985751, 27538604, 29474836, 18546365, 16545482, 19478085, 19251978, 30167885, 24642831, 32445240, 32964447)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000610294.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.000069	not provided	not provided

From Athena Diagnostics, SCV001145154.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in individuals with autosomal recessive POLG-related disorders. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19478085) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001149562.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

POLG: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808637.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001971371.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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