Variant: NM_002693.3(POLG):c.3286C>T

CA316756

206556 (ClinVar)

Gene: POLG

Condition: mitochondrial disease

Inheritance Mode: Autosomal recessive inheritance

UUID: e8e0afbe-c398-4ea8-bc33-403b83acafc5

HGVS expressions

NM_002693.3:c.3286C>T
NM_002693.3(POLG):c.3286C>T
ENST00000268124.11:c.3286C>T
ENST00000530292.3:n.2887C>T
ENST00000635986.2:c.*356C>T
ENST00000636774.1:c.*1853C>T
ENST00000637238.1:n.2095C>T
ENST00000637264.1:n.2358C>T
ENST00000666746.1:n.2863C>T
ENST00000672071.1:n.3484C>T
ENST00000672695.1:n.463C>T
ENST00000672923.2:n.3286C>T
ENST00000268124.9:c.3286C>T
ENST00000442287.6:c.3286C>T
ENST00000530292.2:n.370C>T
ENST00000631044.2:c.*2710C>T
NM_001126131.1:c.3286C>T
NM_002693.2:c.3286C>T
NM_001126131.2:c.3286C>T
NC_000015.10:g.89318737G>A
CM000677.2:g.89318737G>A
NC_000015.9:g.89861968G>A
CM000677.1:g.89861968G>A
NC_000015.8:g.87662972G>A
NG_008218.1:g.21059C>T
NG_011736.1:g.79775G>A
NG_008218.2:g.21059C>T

Likely Pathogenic

• Met criteria codes: PM3_Strong PP3 PM2

• Not Met criteria codes: PP4

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The c.3286 C>T (p.Arg1096Cys) variant in POLG is seen at an allele frequency of 0.00001 in gnomAd and 0.00002 in ExAC with no homozygotes (PM2). This variant has a Revel score of 0.837 (PP3). There are 7 cases in the literature reported with an Alpers phenotype in individuals who are homozygous for the c.3286 C>T (p.Arg1096Cys) (PM3_strong; PMID:21305355; PMID:21880868; PMID:18546365). There are also 6 cases reported with other pathogenic variants with phasing unknown 2 siblings reported compound heterozygous with Thr914Pro, another reported with Trp748Ser, another cases with Leu591Phe, another case with Ala467Thr, and another case with Gly848Ser. Each case was reported with POLG related disease with Alpers, liver related disease, and other neurological phenotypes (PM3_strong; PMID:18487244; PMID:30021052; PMID:24265579; PMID:27111573; PMID:21880868). In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PM2, PP3, PM3_strong

Met criteria codes

• PM3_Strong: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: Revel score 0.837
• PM2: Allele frequency < 0.05% and no homzygotes gnomAD 0.00001 ExAC 0.00002

Not Met criteria codes

• PP4: PMID 21880868 and PMID 18487244

Approved on: 2021-05-23

Published on: 2021-05-23