15-89318737-G-C

Position:

• chr15-89318737-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002693.3(POLG):​c.3286C>G​(p.Arg1096Gly) variant causes a missense change. 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.23

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 16 ACMG points.

• PM1: In a helix (size 28) in uniprot entity DPOG1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002693.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 15-89318737-G-C is Pathogenic according to our data. Variant chr15-89318737-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206555.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.3286C>G	p.Arg1096Gly	missense_variant	21/23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.3286C>G	p.Arg1096Gly	missense_variant	21/23		NP_001119603.1
POLGARF	NM_001406557.1	c.*2558C>G		3_prime_UTR_variant	21/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3286C>G	p.Arg1096Gly	missense_variant	21/23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2013	p.Arg1096Gly (CGT>GGT): c.3286 C>G in exon 21 of the POLG gene (NM_002693.2). A R1096G missense change was identified in the POLG gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Other missense mutations at the same positions (R1096H and R1096C) have been reported previously. R1096H was previously reported in a patient with a clinical diagnosis of Alpers syndrome who had a second POLG mutation on the other chromosome (Horvath et al., 2006), while R1096C is a common POLG mutation that has been identified in multiple patients with autosomal recessive POLG-related disorders (Tang et al., 2011). R1096G represents a non-conservative amino acid substitution as a large, positively charged Arginine reside is replaced by a small, uncharged Glycine residue. Therefore, we interpret R1096G to be a pathogenic mutation. The variant is found in DEPLTN-MITOP panel(s). -

Progressive sclerosing poliodystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 07, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1096 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707443, 19752458, 21305355, 21880868, 22189570, 23545419, 24265579). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 206555). This variant has not been reported in the literature in individuals affected with POLG-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1096 of the POLG protein (p.Arg1096Gly). -

Mitochondrial DNA depletion syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 09, 2023

Variant summary: POLG c.3286C>G (p.Arg1096Gly) results in a non-conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. At-least two other missense variants at this codon (p.Arg1096Cys and p.Arg1096His) have been reported in individuals affected with features of the POLG spectrum of disorders supporting a critical role for this amino acid residue in protein function. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251284 control chromosomes. To our knowledge, no occurrence of c.3286C>G in individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.80		Gain of glycosylation at S1095 (P = 0.0291);Gain of glycosylation at S1095 (P = 0.0291);
MVP		0.98
MPC		0.75
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.93
gMVP		0.95

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: rs201732356; hg19: chr15-89861968;