rs796052908

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_002693.3(POLG):c.1270_1271del(p.Leu424GlyfsTer29) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POLG
NM_002693.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.86

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]

POLG links:

POLGARF (HGNC:):

POLGARF links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-89327328-CAG-C is Pathogenic according to our data. Variant chr15-89327328-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 206608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89327328-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLG	NM_002693.3 linkuse as main transcript	c.1270_1271del	p.Leu424GlyfsTer29	frameshift_variant	7/23	ENST00000268124.11
POLGARF	NM_001406557.1 linkuse as main transcript	c.542_543del		3_prime_UTR_variant	7/23
POLG	NM_001126131.2 linkuse as main transcript	c.1270_1271del	p.Leu424GlyfsTer29	frameshift_variant	7/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.1270_1271del	p.Leu424GlyfsTer29	frameshift_variant	7/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250710

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461510

Hom.:

AF XY:

0.00000413

AC XY:

AN XY:

727056

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy

Pathogenic:3

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.1270_1271del (NP_002684.1:p.Leu424GlyfsTer29) [GRCH38: NC_000015.10:g.89327331_89327332del] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12707443 . This variant meets the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predicted null variant in POLG where loss of function is a known mechanism of disease. 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. PM4:This variant causes alteration in the length of expressed protein. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Leu424Glyfs*29) in the POLG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365). This variant is present in population databases (rs796052908, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 12707443, 18546365). ClinVar contains an entry for this variant (Variation ID: 206608). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2017	c.1270_1271delCT: p.Leu424GlyfsX29 (L424Gfsx29) in exon 7 of the POLG gene (NM_002693.2). The normal sequence with the bases that are deleted in braces is: GACT{CT}GGCC.The c.1270_1271delCT mutation in the POLG gene has been reported in a child with Alpers syndrome and in an individual with adult-onset progressive external ophthalmoplegia (PEO) and multiple mtDNA deletions, both of whom had a second identified mutation in the POLG gene (Wong et al., 2008; Agostino et al., 2003). The deletion causes a frameshift starting with codon Leucine 424, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Leu424GlyfsX29. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in INFANT-EPI panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2021	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in trans with a pathogenic POLG variant in at least one individual with clinical features associated with this gene. -

Generalized epilepsy;C0028754:Obesity;C0557874:Global developmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Claritas Genomics

Nov 28, 2016

The c.1270_1271delCT (p.Leu424Glyfs*29) missense variant in the POLG gene is previously reported in the literature and is expected to be causative of disease, typically as a recessive disorder. Homozygous or compound heterozygous pathogenic variants in this gene are associated with a range of mitochondrial conditions including, Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy syndrome (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), mitochondrial DNA depletion syndrome 4B (MNGIE type), mitochondrial ataxia neuropathy spectrum (includes SANDO and SCAE) and progressive external ophthalmoplegia. Progressive external ophthalmoplegia can also be inherited in an autosomal dominant manner. These conditions are known to have variable expressivity, including a wide range in age of onset as well as reduced penetrance. This deletion of two basepairs results in a shift in the reading frame at position p.Leu424 and introduces a premature stop codon 28 positions downstream, which is predicted to result in protein truncation or nonsense mediated decay. It has been reported in the compound heterozygous state in one individual with adult-onset progressive external ophthalmoplegia and one child with Alpers syndrome. It has not been observed in the 1000 Genomes, ExAC, or NHLBI Exome Sequencing Project control databases. Therefore, due to the predicted loss-of-function effect of the variant and prior reports in the literature, it is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over