NM_002693.3(POLG):c.2542G>A (p.Gly848Ser) AND multiple conditions

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 30, 2021
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:: RCV001027839.10

Allele description [Variation Report for NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)]

NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)

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.2542G>A (p.Gly848Ser)

Other names:

p.G848S:GGC>AGC; NM_001126131.1(POLG):c.2542G>A(p.Gly848Ser); NM_002693.2(POLG):c.2542G>A(p.Gly848Ser)

HGVS:

NC_000015.10:g.89321792C>T
NG_008218.2:g.18004G>A
NM_001126131.2:c.2542G>A
NM_002693.3:c.2542G>AMANE SELECT
NP_001119603.1:p.Gly848Ser
NP_002684.1:p.Gly848Ser
NP_002684.1:p.Gly848Ser
LRG_765t1:c.2542G>A
LRG_765:g.18004G>A
LRG_765p1:p.Gly848Ser
NC_000015.9:g.89865023C>T
NM_001126131.1:c.2542G>A
NM_002693.2:c.2542G>A
P54098:p.Gly848Ser

Protein change:

G848S; GLY848SER

Links:

UniProtKB: P54098#VAR_023675; OMIM: 174763.0006; dbSNP: rs113994098

NCBI 1000 Genomes Browser:

rs113994098

Molecular consequence:

NM_001126131.2:c.2542G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.2542G>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

Name:: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Synonyms:: PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 1
Identifiers:: MONDO: MONDO:0024528; MedGen: C1834846; OMIM: 157640

Name:: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (PEOB1)
Synonyms:: Cerebellar ataxia infantile with progressive external ophthalmoplegia; Progressive external ophthalmoplegia, autosomal recessive 1
Identifiers:: MONDO: MONDO:0009783; MedGen: C4225153; Orphanet: 254886; OMIM: 258450

Name:: Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO)
Synonyms:: SENSORY ATAXIC NEUROPATHY WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Epilepsy, progressive myoclonic, type 5
Identifiers:: MONDO: MONDO:0011835; MedGen: C1843851; OMIM: 607459

Name:: Mitochondrial DNA depletion syndrome 4b
Synonyms:: MNGIE, POLG-RELATED; Mitochondrial Neurogastrointestinal Encephalopathy Disease, POLG-Related; Mitochondrial DNA depletion syndrome 4B, MNGIE type
Identifiers:: MONDO: MONDO:0013350; MedGen: C3150914; Orphanet: 298; OMIM: 613662

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001190459	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001984826	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 21, 2020)	germline	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

SCV001190459

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 30, 2021)

germline

clinical testing

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

SCV001984826

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 21, 2020)

germline

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV001190459.2

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

Description

POLG NM_002693.2 exon 16 p.Gly848Ser (c.2542G>A): This variant has been reported in the literature in the compound heterozygous or homozygous state in several individuals with autosomal recessive progressive external opthalmoplegia as well as a wide variety of additional POLG-related phenotypes (Lamantea 2002 PMID:12210792, Weiss 2010 PMID:20513108, Milone 2011 PMID:21670405, Tang 2011 PMID:21880868, Scalais 2012 PMID:22342071, Uusimaa 2013 PMID:23448099, Simon 2014 PMID:2014 PMID:24272679). Literature suggests that this variant is one of the most common pathgenic variants in the POLG gene (Hakonen, 2007 PMID:17426723, Tang 2011 PMID:21880868). This variant is present in 0.03% (40/129136) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-89865023-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13502). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies indicate that this variant leads to decreased enzyme activity and reduced DNA binding affinity (Kasivishwanathan 2009 PMID:19478085). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.

#	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001984826.1

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

Description

This variant has been previously reported as a compound heterozygous change in multiple patients with autosomal recessive POLG-related disorders including Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, optic Atrophy, intractable epilepsy and early onset epileptic encephalopathy (PMID: 12210792, 22189570, 23448099, 30552426, 30423451, 29655203). Functional characterization indicates that the p.Gly848Ser variant, which is located in the thumb domain of the protein and affects a conserved glycine residue upstream of motif polA, results in <1% polymerase activity, and in a defect in DNA binding function (PMID: 19478085). In addition, studies in model organisms indicated that the yeast-equivalent of the p.Gly848Ser variant results in high mtDNA instability (PMID: 17980715). The p.Gly848Ser variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.017% (48/282794) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.2542G>A (p.Gly848Ser) variant on protein function. Based on the available evidence, the c.2542G>A (p.Gly848Ser) variant is classified as Pathogenic.

#	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

Last Updated: May 7, 2024

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