NM_002693.3(POLG):c.3643+2T>C AND Progressive sclerosing poliodystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 21, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001037377.7

Allele description [Variation Report for NM_002693.3(POLG):c.3643+2T>C]

NM_002693.3(POLG):c.3643+2T>C

Gene:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.3643+2T>C

HGVS:

NC_000015.10:g.89317374A>G
NG_008218.2:g.22422T>C
NG_011736.1:g.78412A>G
NM_001126131.2:c.3643+2T>C
NM_002693.3:c.3643+2T>CMANE SELECT
LRG_765t1:c.3643+2T>C
LRG_500:g.78412A>G
LRG_765:g.22422T>C
NC_000015.9:g.89860605A>G
NM_002693.2(POLG):c.3643+2T>C
NM_002693.2:c.3643+2T>C

Links:

dbSNP: rs1335880349

NCBI 1000 Genomes Browser:

rs1335880349

Molecular consequence:

NM_001126131.2:c.3643+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_002693.3:c.3643+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:: ALPERS PROGRESSIVE INFANTILE POLIODYSTROPHY; NEURONAL DEGENERATION OF CHILDHOOD WITH LIVER DISEASE, PROGRESSIVE; Alpers disease; 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
SCV001200788	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19500334, 17576681, 9536098, 20691285, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001200788

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Citations

PubMed

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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001200788.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

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 0.0009%). Disruption of this splice site has been observed in individual(s) with POLG-related conditions (PMID: 19500334, 20691285). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 597808). 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.

#	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: Feb 25, 2025

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