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:: RCV003516366.2

Allele description [Variation Report for NM_002693.3(POLG):c.3316G>A (p.Val1106Ile)]

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

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.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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004297673	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15349879, 26077851, 33469851, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004297673

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 4, 2024)

germline

clinical testing

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

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

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004297673.1

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

#	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: Sep 29, 2024

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