rs113994099

Positions:

• chr15-89320883-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000268124.11(POLG):​c.2864A>G​(p.Tyr955Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y955H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLG ENST00000268124.11 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.67

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:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000268124.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-89320884-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3068318.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 15-89320883-T-C is Pathogenic according to our data. Variant chr15-89320883-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89320883-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.2864A>G	p.Tyr955Cys	missense_variant	18/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.*2136A>G		3_prime_UTR_variant	18/23		NP_001393486.1
POLG	NM_001126131.2	c.2864A>G	p.Tyr955Cys	missense_variant	18/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2864A>G	p.Tyr955Cys	missense_variant	18/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461664 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2020	Functional studies demonstrated in the absence of intrinsic proofreading activity, the Y955C variant was associated with increased error rate during DNA synthesis (Ponamarev et al., 2002; Estep et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32161153, 31521625, 30848931, 12210792, 15702133, 21880868, 23673011, 11431686, 28430993, 16595552, 24943079, 27987238, 21228000, 19010300, 12565911, 2067633, 2725645, 11897778, 15258572, 17310215, 17725985, 16940310, 16368709, 23811324, 21696159, 15351195, 31263856) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 06, 2020	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families. -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	POLG: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -

Progressive sclerosing poliodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.2864A>G (NP_002684.1:p.Tyr955Cys) [GRCH38: NC_000015.10:g.89320883T>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). 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. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 955 of the POLG protein (p.Tyr955Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant progressive external ophthalmoplegia (PMID: 11431686, 16595552, 31521625, 32161153). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13495). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial disease Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	Apr 07, 2017	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2004

- -

Mitochondrial DNA depletion syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 21, 2023

Variant summary: POLG c.2864A>G (p.Tyr955Cys) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2864A>G has been reported in the literature in multiple heterozygous individuals affected with progressive external ophthalmoplegia with Mitochondrial DNA Depletion, autosomal dominant with evidence of familial co-segregation (e.g. Lamantea_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced mitochondrial bioenergetics with 10%-<30% of normal growth capability in vitro (e.g. Rahman_2022). The following publications have been ascertained in the context of this evaluation (PMID: 12210792, 35760101). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.98		Loss of MoRF binding (P = 0.0908);Loss of MoRF binding (P = 0.0908);
MVP		1.0
MPC		0.74
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.98

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

Other links and lift over

dbSNP: rs113994099; hg19: chr15-89864114;