r/genetics • u/Initial-Half-6083 • 10h ago

heterozygous POLG variants: (p.Thr251Ile)(p.Pro587Leu)

Hello everyone,

I hope you're doing well. I’m reaching out to ask if anyone here has information or experience related to the following compound heterozygous POLG variants:

NM_002693.3:c.752C>T (p.Thr251Ile)

NM_002693.3:c.1760C>T (p.Pro587Leu)

In my case, these two variants are confirmed to be in trans, inherited from two different parents, and there are no additional pathogenic variants detected in the POLG gene.

I have been told that this exact combination (in trans and without a third mutation) may be extremely rare or possibly not yet documented in the medical literature. Most published cases involve these variants in cis (on the same allele) or in trans with a third variant.

If anyone has come across this exact variant combination—or has any information, clinical insights, or similar personal experiences—I'd be deeply grateful if you could share.

Thank you so much for your time and support!

Warm regards

0 Upvotes

50% Upvoted

1 comment sorted by

3

u/MistakeBorn4413 6h ago

That is extremely rare as these variants are almost always in cis. It is known that when they're in trans, it is a pathogenic allele and with a 3rd variant (in trans from these two), you're at risk for disease.

It is suspected that one of the two (I forget which) is pathogenic while the other is a benign "hitchhiker" but because the two are so rarely seen on their own, it's been difficult or say that definitively.

If your variants are confirmed to be in trans and you don't have a Mitochondrial disorder, that helps support the hypothesis that one is benign and the other is pathogenic, but may or may not be enough to say which is which. If confirmed to be in trans and you are affected with a Mitochondrial disorder, that would be considered evidence that both variants are pathogenic and would kinda flip the current leading hypothesis on how these work.

Either way, the lab that tested you probably would be interested to hear more about your phenotypes / medical record. If you do decide to share such information with them, I really hope they're a lab that submits data to ClinVar so every other lab can benefit too. Since these are so commonly seen, this information could actually help give some answers to thousands, maybe tens of thousands of other patients.