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NM_002693.3(POLG):c.3316G>A (p.Val1106Ile) AND Progressive sclerosing poliodystrophy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 4, 2024
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:
RCV003516366.1

Allele description

NM_002693.3(POLG):c.3316G>A (p.Val1106Ile)

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.3316G>A (p.Val1106Ile)
HGVS:
  • NC_000015.10:g.89318707C>T
  • NG_008218.2:g.21089G>A
  • NG_011736.1:g.79745C>T
  • NM_001126131.2:c.3316G>A
  • NM_002693.3:c.3316G>AMANE SELECT
  • NP_001119603.1:p.Val1106Ile
  • NP_002684.1:p.Val1106Ile
  • NP_002684.1:p.Val1106Ile
  • LRG_765t1:c.3316G>A
  • LRG_500:g.79745C>T
  • LRG_765:g.21089G>A
  • LRG_765p1:p.Val1106Ile
  • NC_000015.9:g.89861938C>T
  • NM_002693.2:c.3316G>A
Protein change:
V1106I
Molecular consequence:
  • NM_001126131.2:c.3316G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.3316G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:
Alpers disease; Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis; Alpers progressive infantile poliodystrophy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008758; MedGen: C0205710; Orphanet: 726; OMIM: 203700

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004297673Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 4, 2024) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene.

Lamantea E, Zeviani M.

Ann Neurol. 2004 Sep;56(3):454-5. No abstract available.

PubMed [citation]
PMID:
15349879

Yeast model analysis of novel polymerase gamma variants found in patients with autosomal recessive mitochondrial disease.

Kaliszewska M, Kruszewski J, Kierdaszuk B, Kostera-Pruszczyk A, Nojszewska M, Łusakowska A, Vizueta J, Sabat D, Lutyk D, Lower M, Piekutowska-Abramczuk D, Kaniak-Golik A, Pronicka E, Kamińska A, Bartnik E, Golik P, Tońska K.

Hum Genet. 2015 Sep;134(9):951-66. doi: 10.1007/s00439-015-1578-x. Epub 2015 Jun 16.

PubMed [citation]
PMID:
26077851
PMCID:
PMC4529462
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004297673.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1106 of the POLG protein (p.Val1106Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with progressive external ophthalmoplegia (PMID: 15349879). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. This variant disrupts the p.Val1106 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26077851, 33469851). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: May 12, 2024