Submissions for variant NM_002693.3(POLG):c.3640C>T (p.Gln1214Ter)

gnomAD frequency: 0.00001  dbSNP: rs781256643

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000579250	SCV000680672	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Reported previously in an individual with dementia, muscle weakness, easy fatigability, ophthalmoparesis, myopathy, mitochondrial changes, abnormal muscle histology, and abnormal electromyogram/nerve conduction velocity; this individual was also heterozygous for another variant in POLG, although the phase of these variants was not reported (Tang et al., 2011).; Nonsense variant predicted to result in protein truncation as the last 26 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32347949, 34426522, 21880868)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758431	SCV000887135	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3640C>T (NP_002684.1:p.Gln1214Ter) [GRCH38: NC_000015.10:g.89317379G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). 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. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758431	SCV001506455	uncertain significance	Progressive sclerosing poliodystrophy	2023-05-22	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 488798). This premature translational stop signal has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 21880868). This variant is present in population databases (rs781256643, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gln1214*) in the POLG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the POLG protein.
Revvity Omics, Revvity	RCV000579250	SCV002024712	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000758431	SCV004205854	likely pathogenic	Progressive sclerosing poliodystrophy	2024-01-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000579250	SCV005411114	uncertain significance	not provided	2024-04-11	criteria provided, single submitter	clinical testing	PM2_moderate, PVS1_moderate