rs121918051

Positions:

• chr15-89320878-C-A
• chr15-89320878-C-G

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.2869G>T​(p.Ala957Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A957P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLG ENST00000268124.11 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.57

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, 8 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 chr15-89320878-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 15-89320878-C-A is Pathogenic according to our data. Variant chr15-89320878-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.2869G>T	p.Ala957Ser	missense_variant	18/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.*2141G>T		3_prime_UTR_variant	18/23		NP_001393486.1
POLG	NM_001126131.2	c.2869G>T	p.Ala957Ser	missense_variant	18/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2869G>T	p.Ala957Ser	missense_variant	18/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive sclerosing poliodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 957 of the POLG protein (p.Ala957Ser). 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: 12210792). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13508). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 15258572, 23208208). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 05, 2022	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.96		Gain of glycosylation at A957 (P = 0.0467);Gain of glycosylation at A957 (P = 0.0467);
MVP		0.98
MPC		0.63
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.86

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: rs121918051; hg19: chr15-89864109;