NM_002693.3:c.1399G>A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PM5 PP5

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 frequency of 0.00101 in 1,614,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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)."; 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).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A467D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:55 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial DNA depletion syndrome 4a

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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: Other missense variant is known to change same aminoacid residue: Variant chr15-89327200-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2072863.
• PP5: Variant 15-89327201-C-T is Pathogenic according to our data. Variant chr15-89327201-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13496.

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.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

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000519 AC: 63

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
18	-	-	not provided (18)
10	-	-	Progressive sclerosing poliodystrophy (10)
4	-	-	POLG-related disorder (5)
4	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (4)
3	-	-	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (3)
2	-	-	POLG-Related Spectrum Disorders (2)
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)
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;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	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
Polyphen		1.0	D
Vest4		0.92
MVP		0.98
MPC		0.65
ClinPred		0.16	T
GERP RS		5.0
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

Other links and lift over

dbSNP: rs113994095; hg19: chr15-89870432;