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.3573G>T (p.Lys1191Asn)

CA10602282

426681 (ClinVar)

Gene: POLG

Condition: mitochondrial disease

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a57c4294-b4fc-47f9-a409-2182e7ab5ba1

HGVS expressions

NM_002693.2:c.3573G>T

NM_002693.2(POLG):c.3573G>T (p.Lys1191Asn)

ENST00000268124.11:c.3573G>T

ENST00000530292.3:n.3273G>T

ENST00000635986.2:c.*643G>T

ENST00000636774.1:c.*2177G>T

ENST00000637042.1:n.97G>T

ENST00000637238.1:n.2481G>T

ENST00000637264.1:n.2585G>T

ENST00000666746.1:n.3150G>T

ENST00000672071.1:n.4775G>T

ENST00000672695.1:n.1352G>T

ENST00000672923.2:n.3573G>T

ENST00000268124.9:c.3573G>T

ENST00000442287.6:c.3573G>T

ENST00000526671.1:n.383G>T

ENST00000530292.2:n.756G>T

ENST00000631044.2:c.*2997G>T

NM_001126131.1:c.3573G>T

NM_001126131.2:c.3573G>T

NM_002693.3:c.3573G>T

NC_000015.10:g.89317446C>A

CM000677.2:g.89317446C>A

NC_000015.9:g.89860677C>A

CM000677.1:g.89860677C>A

NC_000015.8:g.87661681C>A

NG_008218.1:g.22350G>T

NG_011736.1:g.78484C>A

NG_008218.2:g.22350G>T

Likely Pathogenic

PP3 PM2 PM3_Strong

BS2

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.3573 G>T (K1191N) variant in POLG is absent in population databases (PM2 met). Computational prediction tool Revel score 0.876 (PP3 met Revel score > 0.75). This variant has been seen in 3 cases as compound heterozygotes. Two cases with Ala467Thr presenting with Alpers syndrome and one with c.752 C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM3_strong met; PMID: 16621917; PMID: 21880868; PMID: 19538466). In summary, this variant is characterized as a likely pathogenic variant for primary mitochondrial disease inherited in a autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3.

PP3

Revel score > 0.75 Revel score for variant 0.876

PM2

Absent from databases

PM3_Strong

3 cases all seen in as compound heterozygotes 2 with A467T and 1 with c.752 C>T (T251I) / c.1760 C>T (P587L). 2 cases had Alpers and 1 case had CPEO spectrum disorder.

BS2

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

Approved on: 2021-05-06

Published on: 2021-05-06

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