Submissions for variant NM_002693.3(POLG):c.1904C>T (p.Pro635Leu)

gnomAD frequency: 0.00007  dbSNP: rs773994204

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705035	SCV000242174	uncertain significance	not provided	2024-04-10	criteria provided, single submitter	clinical testing	Reported in trans with a benign variant in POLG in an individual with colorectal cancer; no further clinical information was provided (PMID: 25850945); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25850945)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758443	SCV000887153	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1904C>T (NP_002684.1:p.Pro635Leu) [GRCH38: NC_000015.10:g.89325495G>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758443	SCV001381642	uncertain significance	Progressive sclerosing poliodystrophy	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 635 of the POLG protein (p.Pro635Leu). This variant is present in population databases (rs773994204, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206503). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001705035	SCV002545307	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001705035	SCV005193984	uncertain significance	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV001705035	SCV005411130	uncertain significance	not provided	2023-10-17	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV004732761	SCV005348738	uncertain significance	POLG-related disorder	2024-04-11	no assertion criteria provided	clinical testing	The POLG c.1904C>T variant is predicted to result in the amino acid substitution p.Pro635Leu. To our knowledge, this variant has not been reported in individuals with POLG-related disease. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.