NM_002693.3(POLG):c.679C>T (p.Arg227Trp) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 16, 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:: RCV000255169.6

Allele description [Variation Report for NM_002693.3(POLG):c.679C>T (p.Arg227Trp)]

NM_002693.3(POLG):c.679C>T (p.Arg227Trp)

Genes:

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

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.679C>T (p.Arg227Trp)

HGVS:

NC_000015.10:g.89330257G>A
NG_008218.2:g.9539C>T
NM_001126131.2:c.679C>T
NM_002693.3:c.679C>TMANE SELECT
NP_001119603.1:p.Arg227Trp
NP_002684.1:p.Arg227Trp
NP_002684.1:p.Arg227Trp
LRG_765t1:c.679C>T
LRG_765:g.9539C>T
LRG_765p1:p.Arg227Trp
NC_000015.9:g.89873488G>A
NM_002693.2:c.679C>T
P54098:p.Arg227Trp

Protein change:

R227W; ARG227TRP

Links:

UniProtKB: P54098#VAR_023663; OMIM: 174763.0021; dbSNP: rs121918056

NCBI 1000 Genomes Browser:

rs121918056

Molecular consequence:

NM_001126131.2:c.679C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.679C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000322023	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Oct 8, 2016)	germline	clinical testing	Citation Link,
SCV004229898	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Apr 6, 2023)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 28471437, 25281868, 16957900, 30290626, 31694722, 12707443, 15349879, 19307547, 22277967, 16621917, 26467025
SCV004238110	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322023

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Oct 8, 2016)

germline

clinical testing

Citation Link,

SCV004229898

Athena Diagnostics Inc

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Apr 6, 2023)

unknown

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV004238110

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 16, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

Hikmat O, Tzoulis C, Chong WK, Chentouf L, Klingenberg C, Fratter C, Carr LJ, Prabhakar P, Kumaraguru N, Gissen P, Cross JH, Jacques TS, Taanman JW, Bindoff LA, Rahman S.

Genet Med. 2017 Nov;19(11):1217-1225. doi: 10.1038/gim.2017.35. Epub 2017 Apr 27. Erratum in: Genet Med. 2019 Apr;21(4):1027.

PubMed [citation]

PMID:: 28471437

Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia.

Horga A, Pitceathly RD, Blake JC, Woodward CE, Zapater P, Fratter C, Mudanohwo EE, Plant GT, Houlden H, Sweeney MG, Hanna MG, Reilly MM.

Brain. 2014 Dec;137(Pt 12):3200-12. doi: 10.1093/brain/awu279. Epub 2014 Oct 3.

PubMed [citation]

PMID:: 25281868
PMCID:: PMC4240292

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000322023.5

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

Description

The R227W missense variant in the POLG gene has been reported multiple times previously in individuals with POLG-related disorders who had a second POLG variant identified on the opposite allele (Agostino et al., 2003; Human DNA Polymerase Gamma Mutation Database). It was not observed in approximately 6,500 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 R227W 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, and this substitution occurs at a position that is conserved across species. Therefore, R227W is considered to be a pathogenic variant.

#	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 Athena Diagnostics Inc, SCV004229898.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with POLG-related disorders, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.

#	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 Revvity Omics, Revvity, SCV004238110.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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