Submissions for variant NM_002693.3(POLG):c.2395del (p.Ser799fs)

dbSNP: rs796052919

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188698	SCV000242322	pathogenic	not provided	2014-11-14	criteria provided, single submitter	clinical testing	c.2395delT: p.Ser799LeufsX27 (S799LfsX27) in exon 14 of the POLG gene (NM_002693.2). The normal sequence with the base that is deleted in braces is: GATT{T}CTTT. The c.2395delT mutation in the POLG gene causes a frameshift starting with codon Serine 799, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Ser799LeufsX27. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been previously reported to our knowledge, other frameshift mutations have been reported in the POLG gene in association with POLG-related disorders. Therefore, c.2395delT is considered a disease-causing mutation. The variant is found in INFANT-EPI panel(s).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758426	SCV000887130	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2395del (NP_002684.1:p.Ser799LeufsTer27) [GRCH38: NC_000015.10:g.89322775del] 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.
Baylor Genetics	RCV000758426	SCV004205882	likely pathogenic	Progressive sclerosing poliodystrophy	2023-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758426	SCV004399623	pathogenic	Progressive sclerosing poliodystrophy	2023-08-09	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: 206632). This variant has not been reported in the literature in individuals affected with POLG-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser799Leufs*27) 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).