POLG Pathogenicity Prediction Server

POLG Pathogenicity Prediction Server

Mutation Query

Allele 1:

K601E

Allele 2:

D122Y, Q1236H, Y837C

Allelic information known

Amino Acid Residue Information

1226018371236

Residue D122

Cluster assignment:

SNP

Cluster description:

Single Nucleotide Polymorphism

POLG domain:

N-Terminal domain

Residue K601

Cluster assignment:

Cluster 2

Cluster description:

Upstream DNA binding channel

Subcluster:

2C (residues 561-617)

Subcluster description:

Subcluster 2C contains motif 1, which in Pol I was shown to fold into a loop that binds DNA in the channel (Loh and Loeb, 2005). Motif 1, together with subcluster 2D, form the major face of the putative DNA binding channel.

POLG domain:

Spacer domain

Residue Y837

Cluster assignment:

SNP

Cluster description:

Single Nucleotide Polymorphism

POLG domain:

Polymerase domain

Residue Q1236

Cluster assignment:

SNP

Cluster description:

Single Nucleotide Polymorphism

POLG domain:

Polymerase domain

Mutation Information

Number of patients:

(with K601E)

2

Found together with:

Non-allelic

%

Show Patient Data

Number of patients:

(with D122Y)

2

Found together with:

Non-allelic

%

Allelic

%

Show Patient Data

Number of patients:

(with Q1236H)

12

Found together with:

Non-allelic

8

8

8

%

Allelic

8

8

8

8

%

PNF=Putatively Non-Functional enzyme

Show Patient Data

Patient data are sorted by mutation combination frequency.

Reference:

Horvath et al, 2006;

1

Description:

Onset at 2 years with encephalopathy, hepatopathy, and myoclonus achalasia. Diagnosed as Alpers.

Mutations:

SNPs:

Q1236H, Q1236H

Age group:

infantile

Age of Onset: 2, Age of Patient: n/a, Age of Death: n/a

Reference:

Wong et al, 2008;

2

Description:

developmental delay, dementia, seizures, Alpers, Family history of Alpers syndrome.

Mutations:

SNPs:

Q1236H, Q1236H

Age group:

infantile

Age of Onset: 1, Age of Patient: n/a, Age of Death: n/a

Reference:

Luoma et al, 2005;

3

Description:

Developed bilateral blepharoptosis in his youth. Neurological examination at the age of 72 showed severe blepharoptosis, lids almost covering his entire pupils. Eye movements were normal, his muscle strength and sensation were good and tendon reflexes were normal, but his gait was unsteady. Early onset ptosis, ataxia

Mutations:

SNPs:

Q1236H

Age group:

adult

Age of Onset: 22, Age of Patient: 73, Age of Death: n/a

Reference:

Luoma et al, 2005;

4

Description:

developed progressive blepharoptosis at the age of 20 and ophthalmoplegia during subsequent years, at 35, the patient developed progressive unsteadiness of gait. She noted fatigue, myalgia and cramps, which were triggered by moderate exercise. At 44, restless legs syndrome, deficits in memory and concentration, and suffered from recurrent episodes of depression, at 46 showed bilateral blepharoptosis, limited eye movements in all directions except downwards, lateral rotatory nystagmus and slight upbeat nystagmus in upward gaze, but no saccades. She had facial muscle weakness, dysarthria and slight proximal muscle weakness. She had glove and stockinglike hypoesthesia, distally impaired vibration sense, absent ankle reflexes and weak other tendon reflexes, as well as mild dysmetria. Her gait was broad-based, with further impairment with eyes closed. Tandem gait was impaired. deltoid muscle showed myopathic features, structurally abnormal mitochondria with para-crystalline inclusions,

Mutations:

SNPs:

Q1236H

Age group:

adult

Age of Onset: 20, Age of Patient: 46, Age of Death: n/a

Reference:

Luoma et al, 2005;

5

Description:

displays mild bilateral blepharoptosis and slight unsteadiness during tandem gait. Early onset ptosis, ataxia

Mutations:

SNPs:

Q1236H

Age group:

juvenile

Age of Onset: n/a, Age of Patient: 19, Age of Death: n/a

Reference:

Zabalza et al, 2014;

6

Description:

Unsteady walk, and showed tremor in both legs when standing. Difficulty in concentrating. Dysarthria. No deep tendon reflexes were evident. Sensory axonal neuropathy. Hyperintensities in images of the subcortical frontal and temporal white substances. myoclonia and tonic-clonic seizures. sensory axonal neuropathy in the lower limbs, moderate dysarthria, and an ataxic gait.

Mutations:

K601E

SNPs:

D122Y, Q1236H, Y837C

Age group:

adult

Age of Onset: 56, Age of Patient: 61, Age of Death: n/a

Reference:

Zabalza et al, 2014;

7

Description:

ataxia, dysarthria and sensory axonal polyneuropathy. At age 52, the patient developed instability upon walking and paraesthesia in lower limbs, when no other symptoms were apparent. Clinical examination at age 67 revealed dysarthria, gait ataxia, hyporeflexia and tactile hypoestesia. Atrophy of the cerebellar hemispheres. Cognitive decline. left hemiparesis related to a non-traumatic subdural haematoma that required neurosurgical treatment, and began to experience myoclonus and tonic-clonic seizures. weak bilateral palpebral ptosis.

Mutations:

K601E

SNPs:

D122Y, Q1236H, Y837C

Age group:

adult

Age of Onset: 52, Age of Patient: 67, Age of Death: n/a

Reference:

Taanman et al, 2009;

8

Description:

Hypotonia at 8 weeks, seizures, hepatopathy, lactic acidemia, died of liver failure. 9% mtDNA copy number in muscle, 11% mtDNA copy number in liver.

Mutations:

SNPs:

E1143G, Q1236H

Age group:

infantile

Age of Onset: 0.1, Age of Patient: n/a, Age of Death: 0.8

Reference:

Pagnamenta et al, 2006;

9

Description:

Presented with ptosis and PEO, in early 20’s, premature ovarian failure at 28 years. proximal muscle weakness, exertional dyspnoea and sensory ataxia, Peripheral neuropathy

Mutations:

SNPs:

Q1236H

Age group:

adult

Age of Onset: 22, Age of Patient: 33, Age of Death: n/a

Reference:

Luoma et al, 2007;

10

Description:

Parkinsons disease, tremor, rigidity, hypo-/ bradykinesia.

Mutations:

SNPs:

Q1236H, R722H

Age group:

adult

Age of Onset: 66, Age of Patient: 77, Age of Death: n/a

Reference:

Luoma et al, 2007;

11

Description:

Parkinsons disease, tremor, rigidity, hypo-/ bradykinesia. Ischemic Heart Disease, atrial fibrillation, hypertension

Mutations:

SNPs:

Q1236H, Y831C

Age group:

adult

Age of Onset: 70, Age of Patient: 79, Age of Death: n/a

Reference:

Wong et al, 2008;

12

Description:

Alpers, chorea, microcephaly, leukodystrophy, Seizures, Dementia, developmental delay.

Mutations:

SNPs:

PNF, Q1236H

Age group:

infantile

Age of Onset: 1.5, Age of Patient: n/a, Age of Death: n/a

Number of patients:

(with Y837C)

2

Found together with:

Non-allelic

%

Allelic

%

Show Patient Data

Pathogenicity Information

Database patient data is inconclusive about the dominant status of mutation K601E.

See full list of putatively-dominant POLG mutations

Database patient data suggest that Q1236H is a known SNP.This mutation is unlikely to cause a POLG-related syndrome.

See full list of known POLG SNPs.

The following information is based on PON-P2 mutation pathogenicity prediction software results.

Cluster 2 mutation with a non-cluster-mapping mutation (SNP) Y837C

PON-P2 predictions results for Y837C
Pathogenicity:	Pathogenic
Probability:	0.903
Standard Error:	0.039
Prediction result is based on sequence analysis only and may not be accurate.

Risk of POLG-related syndromes exists.
Mutation pathogenicity prediction suggests that this mutation could be pathogenic. Predicted chance of pathogenicity is 90.3%.

See further details for residue 837.

All mutations mapping into the pathogenic clusters are in high risk of being pathogenic. As a rule, a patient must have a pathogenic mutation in both of his/ her POLG genes to develop a POLG-related syndrome.

Prediction results for Q1236H gene2, SNP (not considered for pathogenicity information)

Prediction results for D122Y gene2, SNP (not considered for pathogenicity information)

New Mutation Query

Type in POLG mutations:

Allele 1:	Allele 2:

Allelic information known
Allelic information not known

Example input: A467T T914P

Mutations in the same allele can be separated with a comma

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