NM_002693.3(POLG):c.3527C>T (p.Ser1176Leu) AND POLG-Related Spectrum Disorders

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 8, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001375606.1

Allele description [Variation Report for NM_002693.3(POLG):c.3527C>T (p.Ser1176Leu)]

NM_002693.3(POLG):c.3527C>T (p.Ser1176Leu)

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.3527C>T (p.Ser1176Leu)

HGVS:

NC_000015.10:g.89317492G>A
NG_008218.2:g.22304C>T
NG_011736.1:g.78530G>A
NM_001126131.2:c.3527C>T
NM_002693.3:c.3527C>TMANE SELECT
NP_001119603.1:p.Ser1176Leu
NP_002684.1:p.Ser1176Leu
NP_002684.1:p.Ser1176Leu
LRG_765t1:c.3527C>T
LRG_500:g.78530G>A
LRG_765:g.22304C>T
LRG_765p1:p.Ser1176Leu
NC_000015.9:g.89860723G>A
NM_002693.2:c.3527C>T

Protein change:

S1176L

Links:

dbSNP: rs776031396

NCBI 1000 Genomes Browser:

rs776031396

Molecular consequence:

NM_001126131.2:c.3527C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.3527C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: POLG-Related Spectrum Disorders
Identifiers:: MedGen: C4763519

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001572514	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 8, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24508722, 12210792, 15349879, 28480171, 32347949 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001572514

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 8, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.

Farnum GA, Nurminen A, Kaguni LS.

Biochim Biophys Acta. 2014 Jul;1837(7):1113-21. doi: 10.1016/j.bbabio.2014.01.021. Epub 2014 Feb 7.

PubMed [citation]

PMID:: 24508722
PMCID:: PMC4687743

Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.

Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi GP, Zeviani M.

Ann Neurol. 2002 Aug;52(2):211-9.

PubMed [citation]

PMID:: 12210792

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001572514.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: POLG c.3527C>T (p.Ser1176Leu) results in a non-conservative amino acid change located in the palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251486 control chromosomes (gnomAD). The variant, c.3527C>T, has been reported in the literature in a single family, with four compound heterozygous individuals affected with autosomal recessive progressive external ophthalmoplegia (Lamantea_2002, Lamantea_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: May 1, 2024

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