NM_002693.3(POLG):c.2542G>A (p.Gly848Ser) AND POLG-related disorder

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 10, 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:: RCV003231103.10

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:: POLG-related disorder (PEOB)
Synonyms:: POLG-related condition
Identifiers:: MedGen: CN180166

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000607021	GenomeConnect, ClinGen	no classification provided	not provided	unknown, paternal	phenotyping only
SCV004102724	Daryl Scott Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2023)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004120250	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2022)	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

SCV000607021

GenomeConnect, ClinGen

no classification provided

not provided

unknown, paternal

phenotyping only

SCV004102724

Daryl Scott Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 10, 2023)

maternal

clinical testing

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

SCV004120250

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 21, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	1	not provided	not provided	1	not provided	phenotyping only
not provided	paternal	yes	1	not provided	not provided	1	not provided	phenotyping only
not provided	maternal	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 GenomeConnect, ClinGen, SCV000607021.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	phenotyping only	not provided
2	not provided	1	not provided	not provided	phenotyping only	not provided

Description

Variant reported in multiple GenomeConnect participants by GeneDx. Variant interpreted as Pathogenic and reported, most recently, on 2016-10-31. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

From Daryl Scott Lab, Baylor College of Medicine, SCV004102724.1

#	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	maternal	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV004120250.1

#	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.2542G>A variant is predicted to result in the amino acid substitution p.Gly848Ser. This variant has been reported to be causative for a variety of autosomal recessive POLG-associated disorders, such as sensory ataxia neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO), Alpers’ Syndrome, Leigh-like syndrome, intractable epilepsy, and progressive external ophthalmoplegia (PEO) (Gáti et al. 2011. PubMed ID: 22616202; Simon et al. 2014. PubMed ID : 24272679; Uusimaa et al. 2013. PubMed ID : 23448099; Lamantea et al. 2002. PubMed ID: 12210792). The p.Gly848Ser variant protein retained less than 1% of catalytic activity compared to the wild type enzyme (Kasiviswanathan et al. 2009. PubMed ID: 19478085). This variant is reported in 0.0085% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89865023-C-T). We classify this variant 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

Last Updated: May 7, 2024

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