NM_002693.3(POLG):c.2209G>C (p.Gly737Arg) AND Progressive sclerosing poliodystrophy

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 31, 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:: RCV000233045.24

Allele description [Variation Report for NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)]

NM_002693.3(POLG):c.2209G>C (p.Gly737Arg)

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.2209G>C (p.Gly737Arg)

Other names:

p.G737R:GGA>CGA

HGVS:

NC_000015.10:g.89323460C>G
NG_008218.2:g.16336G>C
NM_001126131.2:c.2209G>C
NM_002693.3:c.2209G>CMANE SELECT
NP_001119603.1:p.Gly737Arg
NP_002684.1:p.Gly737Arg
NP_002684.1:p.Gly737Arg
LRG_765t1:c.2209G>C
LRG_765:g.16336G>C
LRG_765p1:p.Gly737Arg
NC_000015.9:g.89866691C>G
NM_001126131.1:c.2209G>C
NM_002693.2:c.2209G>C
P54098:p.Gly737Arg

Protein change:

G737R; GLY737ARG

Links:

UniProtKB: P54098#VAR_058885; OMIM: 174763.0019; dbSNP: rs121918054

NCBI 1000 Genomes Browser:

rs121918054

Molecular consequence:

NM_001126131.2:c.2209G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.2209G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000287668	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16634032, 18546365, 18585914, 19566497, 24725338, 28492532
SCV000536802	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (Jun 21, 2016)	paternal	research	PubMed (1) [See all records that cite this PMID]
SCV000887112	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]
SCV001448830	Knight Diagnostic Laboratories, Oregon Health and Sciences University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059312	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761933	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 8, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004205838	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 28, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations.

Milone M, Brunetti-Pierri N, Tang LY, Kumar N, Mezei MM, Josephs K, Powell S, Simpson E, Wong LJ.

Neuromuscul Disord. 2008 Aug;18(8):626-32. doi: 10.1016/j.nmd.2008.05.009. Epub 2008 Jun 27.

PubMed [citation]

PMID:: 18585914

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000287668.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 737 of the POLG protein (p.Gly737Arg). This variant is present in population databases (rs121918054, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 16634032, 18546365, 18585914, 19566497, 24725338). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13513). 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%. 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 Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536802.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	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, SCV000887112.1

#	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.2209G>C (NP_002684.1:p.Gly737Arg) [GRCH38: NC_000015.10:g.89323460C>G] 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 Knight Diagnostic Laboratories, Oregon Health and Sciences University, SCV001448830.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV002059312.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002761933.1

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

Description

The POLG c.2209G>C variant is classified as Likely Pathogenic (PS4_Moderate, PM3_Strong, PP3, PP5)

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

From Baylor Genetics, SCV004205838.1

#	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: Apr 20, 2024

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