NM_002693.3:c.86C>G

Variant names:

• chr15-89333669-G-C
• rs796052895
• NM_002693.3:c.86C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002693.3(POLG):​c.86C>G​(p.Ser29Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,407,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S29P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.00
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.86C>G	p.Ser29Cys	missense_variant	Exon 2 of 23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001430120.1	c.141C>G	p.Leu47Leu	synonymous_variant	Exon 1 of 2	ENST00000706918.1	NP_001417049.1
POLG	NM_001126131.2	c.86C>G	p.Ser29Cys	missense_variant	Exon 2 of 23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.86C>G	p.Ser29Cys	missense_variant	Exon 2 of 23	1	NM_002693.3	ENSP00000268124.5
POLGARF	ENST00000706918.1	c.141C>G	p.Leu47Leu	synonymous_variant	Exon 1 of 2		NM_001430120.1	ENSP00000516626.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 156754 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000497 AC: 7 AN: 1407236 Hom.: 0 Cov.: 32 AF XY: 0.00000718 AC XY: 5 AN XY: 696828

African (AFR) AF: 0.00 AC: 0 AN: 32272

American (AMR) AF: 0.00 AC: 0 AN: 37636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.000108 AC: 4 AN: 36890

South Asian (SAS) AF: 0.00 AC: 0 AN: 82070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089874

Other (OTH) AF: 0.0000341 AC: 2 AN: 58676

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 29, 2013

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser29Cys (TCC>TGC): c.86 C>G in exon 2 of the POLG gene (NM_002693.2). The Ser29Cys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Ser29Cys is a semi-conservative amino acid substitution as both Serine and Cysteine are uncharged, polar residues; however, the introduction of a Cysteine residue, which impacts disulfide bonding, may affect the secondary structure of the POLG protein. It alters a conserved position in the protein; however, disease-causing missense mutations have not been reported at nearby residues. In silico algorithms are not consistent in their predictions of whether or not Ser29Cys is damaging to the structure/function of the POLG protein. Therefore, based on the currently available information, it is unclear whether Ser29Cys is a disease-causing mutation or a rare benign variant.The variant is found in MITO24,INFANT-EPI panel(s). -

Feb 27, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLG-related disorder Uncertain:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLG c.86C>G variant is predicted to result in the amino acid substitution p.Ser29Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Progressive sclerosing poliodystrophy Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 29 of the POLG protein (p.Ser29Cys). This variant is present in population databases (rs796052895, gnomAD 0.02%). 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: 206550). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. 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. -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Uncertain:1

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	.;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	0.033	D
MutationAssessor	Benign	1.0	L;L
PhyloP100		3.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.37	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.35
MutPred		0.24		Loss of phosphorylation at S29 (P = 0.0165);Loss of phosphorylation at S29 (P = 0.0165);
MVP		0.91
MPC		0.15
ClinPred		0.26	T
GERP RS		3.8
PromoterAI		-0.0044	Neutral
Varity_R		0.19
gMVP		0.33
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs796052895; hg19: chr15-89876900;