Submissions for variant NM_002693.3(POLG):c.2125C>T (p.Arg709Ter)

dbSNP: rs867038717

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431312	SCV000520838	pathogenic	not provided	2016-12-14	criteria provided, single submitter	clinical testing	The R709X variant in the POLG gene has been reported previously in association with progressive external ophthalmoplegia, in two unrelated affected individual who were heterozygous for the R709X variant and another variant (Di Fonzo et al., 2003; Del Bo et al., 2003). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R709X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R709X as a pathogenic variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758415	SCV000887111	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2125C>T (NP_002684.1:p.Arg709Ter) [GRCH38: NC_000015.10:g.89323847G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:14635118 . This variant meets the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predicted null variant in POLG where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PM4:This variant causes alteration in the length of expressed protein. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758415	SCV001581578	pathogenic	Progressive sclerosing poliodystrophy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg709*) in the POLG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with POLG-related conditions (PMID: 14635118, 30167885). ClinVar contains an entry for this variant (Variation ID: 381519). For these reasons, this variant has been classified as Pathogenic.