chr15-89320857-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP4_StrongBS1_Supporting

The NM_002693.3(POLG):​c.2890C>T​(p.Arg964Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,613,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

11
5
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:9B:1

Conservation

PhyloP100: 7.27
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.028860092).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000433 (66/152276) while in subpopulation EAS AF= 0.0108 (56/5174). AF 95% confidence interval is 0.00856. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.2890C>T p.Arg964Cys missense_variant Exon 18 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkc.2890C>T p.Arg964Cys missense_variant Exon 18 of 23 NP_001119603.1 P54098E5KNU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.2890C>T p.Arg964Cys missense_variant Exon 18 of 23 1 NM_002693.3 ENSP00000268124.5 P54098

Frequencies

GnomAD3 genomes
AF:
0.000434
AC:
66
AN:
152158
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0108
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000685
AC:
172
AN:
251154
Hom.:
1
AF XY:
0.000575
AC XY:
78
AN XY:
135740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00881
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000223
AC:
326
AN:
1461630
Hom.:
0
Cov.:
34
AF XY:
0.000198
AC XY:
144
AN XY:
727128
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00599
Gnomad4 SAS exome
AF:
0.000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.000811
GnomAD4 genome
AF:
0.000433
AC:
66
AN:
152276
Hom.:
1
Cov.:
33
AF XY:
0.000510
AC XY:
38
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0108
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000414
Hom.:
1
Bravo
AF:
0.000366
ExAC
AF:
0.000708
AC:
86
Asia WGS
AF:
0.00549
AC:
19
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:12Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:5
Oct 09, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 13, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported previously in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (PMID: 18546365); Published functional studies demonstrate that R964C polymerase gamma showed reduced activity in vitro compared to wild-type (PMID: 17436221, 27987238); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19364868, 20176107, 25852747, 20206271, 25462018, 19762913, 27987238, 29992832, 30941926, 31180159, 31521625, 31665838, 32165824, 32005694, 33763395, 33300680, 35314707, 35598585, 34426522, 24091540, 21880868, 17436221, 37470284, 37453004, 18546365) -

Dec 01, 2016
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 30, 2024
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. (PMID: 17436221, 19364868, 19887119, 20176107, 25462018, 27987238, 25852747, 37470284) This variant segregates with disease in multiple families. -

Mar 24, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 22, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, PP3, PM3, PS3 -

Progressive sclerosing poliodystrophy Pathogenic:1Uncertain:1Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2018
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -

May 11, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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 Pathogenic:2
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3_VeryStrong+PP4+PS3+BS1 -

Jun 14, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:2
Mar 18, 2016
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: reference population

- -

-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Pathogenic:1Uncertain:1
Oct 28, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: POLG c.2890C>T (p.Arg964Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251154 control chromosomes, predominantly at a frequency of 0.0088 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders phenotype. c.2890C>T has been reported in the literature in several individuals affected with clinical features of POLG-Related Spectrum Disorders without strong evidence for causality (example, Yamanaka_2007, Wong_2008, Strickler_2009, Tang_2011, Ohba_2013, Han_2019, Hu_2020, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 14% of normal polymerase gamma enzyme activity in vitro (example, Yamanaka_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19364868, 31665838, 32348839, 34690748, 24091540, 19762913, 21880868, 18546365, 17436221). ClinVar contains an entry for this variant (Variation ID: 206537). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Mar 30, 2023
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1
Mar 27, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3_MOD,PP3 -

Hereditary spastic paraplegia Pathogenic:1
Dec 01, 2017
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MELAS syndrome Pathogenic:1
-
Pediatric Department, Xiangya Hospital, Central South University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in compound heterozygosity with variant (c.2584G>A) -

Mitochondrial DNA depletion syndrome 4b Pathogenic:1
Jan 03, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206537, PMID:17436221, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21880868, 19762913, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17436221, 19364868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Mitochondrial DNA depletion syndrome 4B (MNGIE type) (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Spinocerebellar atrophy Pathogenic:1
Feb 28, 2019
Codex Genetics Limited
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

- -

Inborn genetic diseases Uncertain:1
Oct 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R964C variant (also known as c.2890C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2890. The arginine at codon 964 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two individuals who were compound heterozygotes for POLG alterations and had a clinical diagnosis of an autosomal recessive POLG-related disorder. One individual was an 8-year-old male diagnosed with mtDNA depletion syndrome, mitochondrial recessive ataxia syndrome, and progressive external ophthalmoplegia (PEO) (Ohba C et al. Neurogenetics. 2013 Nov;14(3-4):225-32). The other individual was a 17-year-old male diagnosed with ataxia neuropathy spectrum (ANS), in addition to cerebellar atrophy, and spinocerebellar ataxia with epilepsy (SCAE) (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). The alteration is location in the polymerase domain and functional studies indicated that there was a decrease in the polymerase activity compared to wild type (Yamanaka H et al. J. Infect. Dis., 2007 May;195:1419-25; Bailey CM et al. Antimicrob. Agents Chemother., 2009 Jun;53:2610-2). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant POLG-related progressive external ophthalmoplegia. -

POLG-related disorder Uncertain:1
Sep 10, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The POLG c.2890C>T variant is predicted to result in the amino acid substitution p.Arg964Cys. This variant has been documented in patients with variable clinical manifestations including Parkinson disease (Hsieh et al. 2019. PubMed ID: 30941926; Kasahara et al. 2017. PubMed ID: 27987238). An in vitro study suggested that this variant may decrease nucleoside analog discrimination and impair the polymerase activity (Bailey et al. 2009. PubMed ID: 19364868). However, this variant has an allele frequency of 0.93% in Eastern Asians, including one homozygote in a large public population database, which may be too frequent to be a primary cause of disease. This variant has also been listed with conflicting interpretations from pathogenic to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/206537/). Although we suspect that this variant may be benign, at this time, we cannot rule out the possibility that this variant may function as a hypomorphic allele, and therefore the clinical significance of this variant is currently classified as uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;D
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
.;D
MetaRNN
Benign
0.029
T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.9
M;M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
1.0
D;D
Vest4
0.90
MVP
0.92
MPC
0.77
ClinPred
0.14
T
GERP RS
5.2
Varity_R
0.64
gMVP
0.81

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: rs201477273; hg19: chr15-89864088; COSMIC: COSV51521275; COSMIC: COSV51521275; API