Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

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

CA393747166

597808 (ClinVar)

Gene: POLG

Condition: mitochondrial disease

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0dc43c7b-f575-49c1-b3fa-717f721349b5

HGVS expressions

NM_002693.2:c.3643+2T>C

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

NC_000015.10:g.89317374A>G

CM000677.2:g.89317374A>G

NC_000015.9:g.89860605A>G

CM000677.1:g.89860605A>G

NC_000015.8:g.87661609A>G

NG_008218.1:g.22422T>C

NG_011736.1:g.78412A>G

NG_008218.2:g.22422T>C

ENST00000268124.11:c.3643+2T>C

ENST00000530292.3:n.3343+2T>C

ENST00000635986.2:c.*713+2T>C

ENST00000636774.1:c.*2247+2T>C

ENST00000637238.1:n.2551+2T>C

ENST00000637264.1:n.2655+2T>C

ENST00000666746.1:n.3220+2T>C

ENST00000672071.1:n.4845+2T>C

ENST00000672695.1:n.1422+2T>C

ENST00000672923.2:n.3643+2T>C

ENST00000268124.9:c.3643+2T>C

ENST00000442287.6:c.3643+2T>C

ENST00000526671.1:n.453+2T>C

ENST00000530292.2:n.826+2T>C

ENST00000631044.2:c.*3067+2T>C

NM_001126131.1:c.3643+2T>C

NM_001126131.2:c.3643+2T>C

NM_002693.3:c.3643+2T>C

Pathogenic

PM3 PM2 PVS1 PP4

Evidence Links 0

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The c.3643+2 T>C variant in POLG has been reported in trans with other another pathogenic variant Trp784Ser in a child with Alpers syndrome (PM3; PMID: 20691285). This variant was found in 0.00001% allele frequency in gnomAD and no homozygotes reported (PM2). Prediction given it affects a donor splice site causing complete skipping of exon 22 this results in disruptions in mRNA (PVS1; PMID 20691285). In summary, this variant meets criteria to be classified as pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2, PM3.

PM3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

Rule < 0.05% gnomAD Allele Frequency: 0.00001 No homozygotes reported

PVS1

Per Invitae lab, this sequence change affects a donor splice site in the last intron (intron 22) of the POLG gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

PP4

mtDNA depletion in patient 2 in liver 14%

Approved on: 2021-05-06

Published on: 2021-05-06

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