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NM_002693.3(POLG):c.915C>G (p.Ser305Arg) AND Inborn genetic diseases

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 30, 2020
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:
RCV002372152.3

Allele description [Variation Report for NM_002693.3(POLG):c.915C>G (p.Ser305Arg)]

NM_002693.3(POLG):c.915C>G (p.Ser305Arg)

Gene:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.3(POLG):c.915C>G (p.Ser305Arg)
Other names:
p.S305R:AGC>AGG
HGVS:
  • NC_000015.10:g.89329051G>C
  • NG_008218.2:g.10745C>G
  • NM_001126131.2:c.915C>G
  • NM_002693.3:c.915C>GMANE SELECT
  • NP_001119603.1:p.Ser305Arg
  • NP_002684.1:p.Ser305Arg
  • NP_002684.1:p.Ser305Arg
  • LRG_765t1:c.915C>G
  • LRG_765:g.10745C>G
  • LRG_765p1:p.Ser305Arg
  • NC_000015.9:g.89872282G>C
  • NM_002693.2:c.915C>G
Protein change:
S305R
Links:
dbSNP: rs769410130
NCBI 1000 Genomes Browser:
rs769410130
Molecular consequence:
  • NM_001126131.2:c.915C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.915C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002684842Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jan 30, 2020) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.

Hakonen AH, Davidzon G, Salemi R, Bindoff LA, Van Goethem G, Dimauro S, Thorburn DR, Suomalainen A.

Eur J Hum Genet. 2007 Jul;15(7):779-83. Epub 2007 Apr 11.

PubMed [citation]
PMID:
17426723

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, Milone M, Cohen BH, Wical B, Ganesh J, Basinger AA, Burton BK, Swoboda K, Gilbert DL, Vanderver A, Saneto RP, Maranda B, Arnold G, Abdenur JE, Waters PJ, Copeland WC.

Hum Mutat. 2008 Sep;29(9):E150-72. doi: 10.1002/humu.20824.

PubMed [citation]
PMID:
18546365
PMCID:
PMC2891192
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002684842.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The p.S305R variant (also known as c.915C>G), located in coding exon 3 of the POLG gene, results from a C to G substitution at nucleotide position 915. The serine at codon 305 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in three individuals with Alpers syndrome who also carried POLG p.A467T (phase was not confirmed) (Hunter MF et al. Pediatr. Neurol., 2011 Nov;45:311-8; Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85; Hakonen AH et al. Eur. J. Hum. Genet., 2007 Jul;15:779-83) as well as in one individual with Alpers syndrome without a second identifiable alteration (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). In addition, this alteration was detected in one individual with generalized seizures, myoclonic jerks, ataxia, and sensory-axonal peripheral neuropathy who also carried POLG p.R627Q and in one individual with muscular hypotonia, status epilepticus, repeated vomiting, severe lactic acidosis, and liver failure who may have also carried POLG p.P1073L (Baruffini E et al. Mitochondrion, 2011 Jan;11:182-90). In two functional studies, authors showed that this alteration significantly reduces DNA binding affinity of the mitochondrial DNA polymerase gamma and results in increased mutability and loss of mitochondrial DNA (Baruffini E et al. Mitochondrion, 2011 Jan;11:182-90; Qian Y et al. Front Genet, 2015 Apr;6:135) This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024