rs113994094

Variant names:

• chr15-89330184-G-A
• rs113994094
• NM_002693.3:c.752C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89330184-G-A
• chr15-89330184-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS3 PM1 PP5 BP4

The NM_002693.3(POLG):​c.752C>T​(p.Thr251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,613,784 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004175333: Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T251P) has been classified as Uncertain significance. The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:45 U:7 O:3
• Conservation: PhyloP100: 2.59
• Publications: 84 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

Specifications for POLG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004175333: Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; the Thr251Ile+Pro587Leu double variant showed a synergistic effect and had more severe dysfunction than the either of the variants alone (PMID: 28154168).; SCV000543870: Experimental studies have shown that this missense change affects POLG function (PMID: 28154168).; SCV005088881: "individually both p.Thr251Ile and p.Pro587Leu substitutions functionally impair pol γ activity. However, results also suggest a synergistic effect in terms of impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity in the double mutant cells suggesting the pathogenicity of these variants." PMID:28154168; SCV005398461: Studies show that this variant reduces thermostability and impairs catalytic activity. The dysfunction is more severe when the variant is in cis with p.(Pro587Leu) (PMID: 28154168).; SCV000847672: Biochemical characterization of T251I mutant revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity; T251I+P587L double mutant showed synergistic effect and had more severe dysfunction than T251I alone (DeBalsi, 2017).; SCV006074180: The variant was often in cis with c.1760C>T (p.Pro587Leu). However, at least one publication reports experimental evidence evaluating an impact on protein function of each variant (DeBalsi_2017). c.752C>T (p.Thr251Ile) in isolation resulted in substantial imparitment of POLG function, resulting in 29% of wild type catalytic activity and a 7.2-fold reduction of endonuclease activity. Combining the variant with c.1760C>T (p.Pro587Leu) resulted in a more severe impairment. PMID: 21138766, 28154168, 25742477
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_002693.3
• PP5: Variant 15-89330184-G-A is Pathogenic according to our data. Variant chr15-89330184-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13503.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13515529). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.752C>T	p.Thr251Ile	missense	Exon 3 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.752C>T	p.Thr251Ile	missense	Exon 3 of 23	NP_001119603.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.*24C>T		downstream_gene	N/A	NP_001417049.1	A0A3B3IS91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.752C>T	p.Thr251Ile	missense	Exon 3 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.752C>T	p.Thr251Ile	missense	Exon 3 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.752C>T	p.Thr251Ile	missense	Exon 3 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00155 AC: 389 AN: 251268 AF XY: 0.00161

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00203 AC: 2965 AN: 1461440 Hom.: 2 Cov.: 32 AF XY: 0.00197 AC XY: 1429 AN XY: 727040

African (AFR) AF: 0.000239 AC: 8 AN: 33476

American (AMR) AF: 0.000961 AC: 43 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86256

European-Finnish (FIN) AF: 0.000546 AC: 29 AN: 53132

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00244 AC: 2715 AN: 1111864

Other (OTH) AF: 0.00169 AC: 102 AN: 60390

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74492

African (AFR) AF: 0.000505 AC: 21 AN: 41586

American (AMR) AF: 0.00105 AC: 16 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00225 Hom.: 2

Bravo AF: 0.00158

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00170 AC: 207

EpiCase AF: 0.00262

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
11	1	-	not provided (12)
8	3	-	Progressive sclerosing poliodystrophy (11)
5	-	-	POLG-related disorder (6)
5	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (5)
2	2	-	Mitochondrial DNA depletion syndrome 4b (4)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Global developmental delay (1)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mitochondrial disease (2)
1	-	-	Mitochondrial DNA depletion syndrome (1)
1	-	-	Mitochondrial DNA depletion syndrome 1 (1)
1	-	-	not specified (1)
1	-	-	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.013	D
MutationAssessor	Benign	0.80	N
PhyloP100		2.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.53
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.34
MVP		0.86
MPC		0.16
ClinPred		0.010	T
GERP RS		3.6
Varity_R		0.031
gMVP		0.34
Mutation Taster		=88/12	disease causing (ClinVar)

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: rs113994094; hg19: chr15-89873415; COSMIC: COSV105090787;