chr15-89330242-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_002693.3(POLG):​c.694C>T​(p.Arg232Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

POLG
NM_002693.3 missense

Scores

8
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.41
Variant links:
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]
POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.863
PP5
Variant 15-89330242-G-A is Pathogenic according to our data. Variant chr15-89330242-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 379796.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLGNM_002693.3 linkuse as main transcriptc.694C>T p.Arg232Cys missense_variant 3/23 ENST00000268124.11 NP_002684.1
POLGARFNM_001406557.1 linkuse as main transcriptc.749C>T p.Ala250Val missense_variant 3/23 NP_001393486.1
POLGNM_001126131.2 linkuse as main transcriptc.694C>T p.Arg232Cys missense_variant 3/23 NP_001119603.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkuse as main transcriptc.694C>T p.Arg232Cys missense_variant 3/231 NM_002693.3 ENSP00000268124 P1
POLGARFENST00000706918.1 linkuse as main transcriptc.749C>T p.Ala250Val missense_variant 2/2 ENSP00000516626 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 18, 2015The R232C variant in the POLG gene has not been reported previously as a pathogenic variantnor as a benign polymorphism, to our knowledge. The R232C substitution was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The R232C variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. This substitution occurs at a position in the exonucleasedomain that is conserved across species. In silico analysis predicts this variant is probably damaging tothe protein structure/function. Missense variants in the same residue and nearby residues (C224Y,R227W/P, R232G/H) have been reported in the Human Gene Mutation Database in association withPOLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of theprotein. We interpret R232C as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
33
DANN
Pathogenic
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
M_CAP
Pathogenic
0.52
D
MetaRNN
Pathogenic
0.86
D
MutationTaster
Benign
1.0
D;D
ClinPred
0.99
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770115219; hg19: chr15-89873473; API