NM_002693.3(POLG):c.3287G>A (p.Arg1096His) AND Progressive sclerosing poliodystrophy

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 14, 2024
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:: RCV000551933.15

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:: 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
SCV000630143	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 16621917, 19752458, 35289132, 20185557, 23208208, 12707443, 21305355, 21880868, 22189570, 23545419, 24265579, 28492532
SCV000887124	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004205855	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 11, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000630143

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 14, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000887124

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 1, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004205855

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 11, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
not provided	unknown	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

Ataxia with ophthalmoplegia or sensory neuropathy is frequently caused by POLG mutations.

Schulte C, Synofzik M, Gasser T, Schöls L.

Neurology. 2009 Sep 15;73(11):898-900. doi: 10.1212/WNL.0b013e3181b78488. No abstract available.

PubMed [citation]

PMID:: 19752458

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV000630143.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1096 of the POLG protein (p.Arg1096His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive Alpers syndrome or progressive external ophthalmoplegia (PMID: 16621917, 19752458, 35289132). ClinVar contains an entry for this variant (Variation ID: 206557). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557, 23208208). This variant disrupts the p.Arg1096 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707443, 21305355, 21880868, 22189570, 23545419, 24265579). 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

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000887124.1

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

Description

The NM_002693.2:c.3287G>A (NP_002684.1:p.Arg1096His) [GRCH38: NC_000015.10:g.89318736C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested 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

From Baylor Genetics, SCV004205855.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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