rs113994101

Positions:

• chr15-89317388-C-CG

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The c.3630dup (p.Gly1211ArgfsTer6) variant in POLG was not in any databases (PM2). This variant results in a frameshift causing a loss of function (PVS1). There are no publications of cases with this variant. In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA341888/MONDO:0044970/014

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLG NM_002693.3 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 0.164

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 Likely_pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.3630dupC	p.Gly1211fs	frameshift_variant	22/23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.3630dupC	p.Gly1211fs	frameshift_variant	22/23		NP_001119603.1
POLGARF	NM_001406557.1	c.*2902dupC		3_prime_UTR_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3630dupC	p.Gly1211fs	frameshift_variant	22/23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1 Other:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	May 06, 2021	The c.3630dup (p.Gly1211ArgfsTer6) variant in POLG was not in any databases (PM2). This variant results in a frameshift causing a loss of function (PVS1). There are no publications of cases with this variant. In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2 -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs113994101; hg19: chr15-89860619;