rs796052919
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002693.3(POLG):c.2395del(p.Ser799LeufsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
POLG
NM_002693.3 frameshift
NM_002693.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.91
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-89322772-GA-G is Pathogenic according to our data. Variant chr15-89322772-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2395del | p.Ser799LeufsTer27 | frameshift_variant | 14/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*1667del | 3_prime_UTR_variant | 14/23 | |||
POLG | NM_001126131.2 | c.2395del | p.Ser799LeufsTer27 | frameshift_variant | 14/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2395del | p.Ser799LeufsTer27 | frameshift_variant | 14/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Progressive sclerosing poliodystrophy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 29, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 01, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2023 | 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). This variant is not present in population databases (gnomAD no frequency). 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: 206632). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2014 | 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). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at