NM_002693.3(POLG):c.1491G>C (p.Gln497His) AND Progressive sclerosing poliodystrophy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000528996.17

Allele description [Variation Report for NM_002693.3(POLG):c.1491G>C (p.Gln497His)]

NM_002693.3(POLG):c.1491G>C (p.Gln497His)

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.1491G>C (p.Gln497His)

Other names:

p.Q497H:CAG>CAC

HGVS:

NC_000015.10:g.89327006C>G
NG_008218.2:g.12790G>C
NM_001126131.2:c.1491G>C
NM_002693.3:c.1491G>CMANE SELECT
NP_001119603.1:p.Gln497His
NP_002684.1:p.Gln497His
NP_002684.1:p.Gln497His
LRG_765t1:c.1491G>C
LRG_765:g.12790G>C
LRG_765p1:p.Gln497His
NC_000015.9:g.89870237C>G
NM_001126131.1:c.1491G>C
NM_002693.2:c.1491G>C
P54098:p.Gln497His

Protein change:

Q497H; GLN497HIS

Links:

UniProtKB: P54098#VAR_023669; OMIM: 174763.0016; dbSNP: rs121918052

NCBI 1000 Genomes Browser:

rs121918052

Molecular consequence:

NM_001126131.2:c.1491G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.1491G>C - 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
SCV000630098	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 21, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15824347, 18546365, 18991199, 21357833, 25025039, 25065347, 26942291, 28492532
SCV000886903	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 1, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1582434, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000630098

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 21, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000886903

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 1, 2018)

germline

clinical testing

PubMed (2)
[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

Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations.

Winterthun S, Ferrari G, He L, Taylor RW, Zeviani M, Turnbull DM, Engelsen BA, Moen G, Bindoff LA.

Neurology. 2005 Apr 12;64(7):1204-8.

PubMed [citation]

PMID:: 15824347

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 (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000630098.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 497 of the POLG protein (p.Gln497His). This variant is present in population databases (rs121918052, gnomAD 0.03%). This missense change has been observed in individual(s) with POLG-related conditions (PMID: 15824347, 18546365, 18991199, 21357833, 25025039, 25065347, 26942291). ClinVar contains an entry for this variant (Variation ID: 13510). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000886903.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The NM_002693.2:c.1491G>C (NP_002684.1:p.Gln497His) [GRCH38: NC_000015.10:g.89327006C>G] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:1582434 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.

#	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: Oct 8, 2024

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