Submissions for variant NM_002693.3(POLG):c.3241C>T (p.Arg1081Ter)

gnomAD frequency: 0.00001  dbSNP: rs767708989

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758278	SCV000886930	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3241C>T (NP_002684.1:p.Arg1081Ter) [GRCH38: NC_000015.10:g.89318963G>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	RCV000758278	SCV002172407	pathogenic	Progressive sclerosing poliodystrophy	2022-11-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 619310). This variant has not been reported in the literature in individuals affected with POLG-related conditions. This variant is present in population databases (rs767708989, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg1081*) 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).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788155	SCV005400325	pathogenic	Mitochondrial disease	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial disease (MONDO#0044970), POLG-related. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants are usually inherited in a recessive manner, however progressive external ophthalmoplegia can also be dominant when heterozygous variants are located in the highly conserved active site of motif B of the polymerase domain (PMID: 30451971). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301791). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v4) (5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been classified as pathogenic by two clinical laboratories (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign