rs113994095

Variant names:

• chr15-89327201-C-T
• rs113994095
• NM_002693.3:c.1399G>A
• POLG p.Ala467Thr

Your query was ambiguous. Multiple possible variants found:

• chr15-89327201-C-T
• chr15-89327201-C-A

GermlineCancer (beta)

Variant summary

Our verdict is

Pathogenic

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 12 classification points (ACMG Germline Pathogenicity v2019): 12P and 0B. PS3PM5PP3_ModeratePP5_Strong

The NM_002693.3(POLG):c.1399G>A (p.Ala467Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00101 (AC=1,637) in the gnomAD database across 1,614,256 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00127. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.47). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000245651: "In vitro functional studies have shown that the Ala467Thr variant leads to loss of wild-type activity and binding affinity (Chan 2005, Luoma 2005)."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.A467D: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2072863) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (sando).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:59 B:1 O:2
• Conservation: PhyloP100: 7.47
• Publications: 223 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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, PanelApp Australia
• mitochondrial DNA depletion syndrome 4b

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

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

Our verdict: Pathogenic. The variant received 12 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000245651: "In vitro functional studies have shown that the Ala467Thr variant leads to loss of wild-type activity and binding affinity (Chan 2005, Luoma 2005)."; SCV002503861: "In vitro assays show reduced enzyme activity and DNA binding for the variant." PMID:15917273, 16024923; SCV004175638: Functional studies have demonstrated a significant reduction (96%) in gamma DNA polymerase enzyme activity in mutant cells compared with wild-type. PMID: 16024923; SCV000630094: Experimental studies have shown that this missense change affects POLG function (PMID: 15917273, 16024923).; SCV000886901: "Well established functional studies show a deleterious effect on POLG." PMID: 25741868; SCV000242281: Published functional studies demonstrate a damaging effect (Kasahara et al., 2016); SCV000614701: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16024923, 27987238); SCV003839906: This sequence change has been associated with reduced enzyme activity (PMID: 20301791).; SCV004564949: Functional studies of the variant protein suggest it has reduced affinity for DNA and has significantly decreased polymerase activity compared to wildtype POLG (Chan 2005, Luoma 2006). PMID: 16024923; SCV000394291: Functional studies have demonstrated that the p.Ala467Thr variant results in a drastically reduced polymerase gamma activity to 4 - 18% of the wild type, reduced DNA binding capability to 14% of the control value, and a reduction in a processivity due to an impaired interaction with the accessory subunit of the enzyme which then slows the rate of DNA synthesis (Chan et al. 2005; Luoma et al. 2005).; SCV002819290: Functional analysis using purified recombinant protein showed the variant had reduced binding affinity to DNA and reduced DNA synthesis activity (14% and 18% of controls, respectively. Luoma_2005).; SCV004116148: "In vitro functional studies have shown that this variant leads to loss of activity and binding affinity (Chan et al. 2005. PubMed ID: 16024923; Luoma et al. 2005. PubMed ID: 15917273; Kasahara et al. 2017. PubMed ID: 27987238)."; SCV005900691: Functional characterization indicates that the c.1399G>A (p.Ala467Thr) variant, which is located near the exonuclease domain in the early linker region of the protein, severely reduces DNA polymerase gamma activity (down to 4% of wild type activity) by compromising the catalytic efficiency of the POLG protein (PMID: 16024923, 15917273).; SCV001984827: Functional characterization indicates that the p.Ala467Thr variant, which is located near the exonuclease domain in the early linker region of the protein, severely reduces DNA polymerase gamma activity (down to 4% of wild type activity) by compromising the catalytic efficiency of the POLG protein (PMID: 16024923, 15917273). In addition, p.Ala467Thr fails to associate with the POLG2 accessory subunit, which leads to stalling at the replication fork and depletion of mtDNA over time (PMID: 16024923, 27987238, 16368709).; SCV000851036: In vitro functional studies demonstrate that the p.A467T mutation results in 4-20% of wild-type DNA polymerase activity and fails to interact with the catalytic accessory subunit resulting in compromised catalytic activity (Chan, 2005).
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.A467D: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2072863)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (59/60 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.1399G>A	p.Ala467Thr	missense	Exon 7 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.1399G>A	p.Ala467Thr	missense	Exon 7 of 23	NP_001119603.1	P54098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.1399G>A	p.Ala467Thr	missense	Exon 7 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.1399G>A	p.Ala467Thr	missense	Exon 7 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.1399G>A	p.Ala467Thr	missense	Exon 7 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000513 AC: 129 AN: 251484 AF XY: 0.000522

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00105 AC: 1537 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00103 AC XY: 748 AN XY: 727244

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00133 AC: 1480 AN: 1112012

Other (OTH) AF: 0.000646 AC: 39 AN: 60396

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000617 AC XY: 46 AN XY: 74514

African (AFR) AF: 0.000168 AC: 7 AN: 41596

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.000627

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	not provided (19)
10	-	-	Progressive sclerosing poliodystrophy (10)
7	-	-	POLG-related disorder (8)
5	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (5)
3	-	-	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (3)
2	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (2)
2	-	-	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 (2)
2	-	-	Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (2)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
1	-	-	Mitochondrial disease (2)
1	-	-	Mitochondrial DNA depletion syndrome 4b (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.9	M
PhyloP100		7.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.055	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.68
Mutation Taster		=0/100	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113994095;

hg19: chr15-89870432;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar