NM_002693.3(POLG):c.3287G>A (p.Arg1096His) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 10, 2017
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:: RCV002314742.9

Allele description [Variation Report for NM_002693.3(POLG):c.3287G>A (p.Arg1096His)]

NM_002693.3(POLG):c.3287G>A (p.Arg1096His)

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.3287G>A (p.Arg1096His)

Other names:

p.R1096H:CGT>CAT

HGVS:

NC_000015.10:g.89318736C>T
NG_008218.2:g.21060G>A
NG_011736.1:g.79774C>T
NM_001126131.2:c.3287G>A
NM_002693.3:c.3287G>AMANE SELECT
NP_001119603.1:p.Arg1096His
NP_002684.1:p.Arg1096His
NP_002684.1:p.Arg1096His
LRG_765t1:c.3287G>A
LRG_500:g.79774C>T
LRG_765:g.21060G>A
LRG_765p1:p.Arg1096His
NC_000015.9:g.89861967C>T
NM_002693.2:c.3287G>A
P54098:p.Arg1096His

Protein change:

R1096H

Links:

UniProtKB: P54098#VAR_058894; dbSNP: rs368435864

NCBI 1000 Genomes Browser:

rs368435864

Molecular consequence:

NM_001126131.2:c.3287G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.3287G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000848987	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 10, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16621917, 17280874, 19752458, 20185557, 20803511, 20843780, 23077218, 23208208, 23873972 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000848987

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 10, 2017)

germline

clinical testing

PubMed (9)
[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

Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

Horvath R, Hudson G, Ferrari G, Fütterer N, Ahola S, Lamantea E, Prokisch H, Lochmüller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Hanna M, Fialho D, et al.

Brain. 2006 Jul;129(Pt 7):1674-84. Epub 2006 Apr 18.

PubMed [citation]

PMID:: 16621917

Depletion of mtDNA: syndromes and genes.

Alberio S, Mineri R, Tiranti V, Zeviani M.

Mitochondrion. 2007 Feb-Apr;7(1-2):6-12. Epub 2006 Dec 5. Review.

PubMed [citation]

PMID:: 17280874

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000848987.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.R1096H variant (also known as c.3287G>A), located in coding exon 20 of the POLG gene, results from a G to A substitution at nucleotide position 3287. The arginine at codon 1096 is replaced by histidine, an amino acid with highly similar properties. In one functional study, this alteration's yeast equivalent was found to cause high mytocondrial dysfunction and decreased polymerase activity leading to mtDNA depletion (Stumpf JD et al. Hum. Mol. Genet., 2010 Jun;19:2123-33). In another functional study, this alteration showed decreased affinity for the DNA substrate and decreased rate of nucleotide incorporation, but increased affinity for the incoming nucleotide (Sohl CD et al. Hum. Mol. Genet., 2013 Mar;22:1074-85). In addition, this alteration has been detected in conjunction with POLG p.R627Q in several individuals with phenotypes including: Alpers syndrome, progressive external ophthalmoplegia (PEO), focal nocturnal motor epilepsy with status epilepticus at one month postpartum, and early-onset cerebellar ataxia with PEO; however, phase was not determined in any of these individuals (Horvath R et al. Brain, 2006 Jul;129:1674-84; Schulte C et al. Neurology, 2009 Sep;73:898-900; Savard M et al. Neurology, 2013 Aug;81:770-1; Schicks J et al. Mov. Disord., 2010 Nov;25:2678-82).This amino acid position is highly 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.

#	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: Jun 2, 2024

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