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NM_002693.3(POLG):c.3643+1G>A AND Progressive sclerosing poliodystrophy

Germline classification:
Pathogenic (2 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:
RCV003463330.3

Allele description [Variation Report for NM_002693.3(POLG):c.3643+1G>A]

NM_002693.3(POLG):c.3643+1G>A

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.3643+1G>A
HGVS:
  • NC_000015.10:g.89317375C>T
  • NG_008218.2:g.22421G>A
  • NG_011736.1:g.78413C>T
  • NM_001126131.2:c.3643+1G>A
  • NM_002693.3:c.3643+1G>AMANE SELECT
  • LRG_500:g.78413C>T
  • LRG_765:g.22421G>A
  • NC_000015.9:g.89860606C>T
Molecular consequence:
  • NM_001126131.2:c.3643+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_002693.3:c.3643+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004205885Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 31, 2024) 		unknownclinical testing

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

SCV004535463Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 6, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Mitochondrial mosaics in the liver of 3 infants with mtDNA defects.

Roels F, Verloo P, Eyskens F, François B, Seneca S, De Paepe B, Martin JJ, Meersschaut V, Praet M, Scalais E, Espeel M, Smet J, Van Goethem G, Van Coster R.

BMC Clin Pathol. 2009 Jun 5;9:4. doi: 10.1186/1472-6890-9-4.

PubMed [citation]
PMID:
19500334
PMCID:
PMC2706255
See all PubMed Citations (7)

Details of each submission

From Baylor Genetics, SCV004205885.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV004535463.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change affects a donor splice site in intron 22 of the POLG gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of POLG-related conditions and/or POLG-related conditions (PMID: 19500334, 20691285, 31359948). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 22 and introduces a new termination codon (PMID: 20691285). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 17, 2024