rs1555452461

Positions:

• chr15-89318613-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002693.3(POLG):​c.3409_3410insG​(p.Val1137GlyfsTer36) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLG NM_002693.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.39

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.

• 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 15-89318613-A-AC is Pathogenic according to our data. Variant chr15-89318613-A-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 423899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.3409_3410insG	p.Val1137GlyfsTer36	frameshift_variant	21/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*2681_*2682insG		3_prime_UTR_variant	21/23
POLG	NM_001126131.2	c.3409_3410insG	p.Val1137GlyfsTer36	frameshift_variant	21/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.3409_3410insG	p.Val1137GlyfsTer36	frameshift_variant	21/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 25, 2017

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2017

A variant that is likely pathogenic has been identified in the POLG gene. The c.3409dupG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3409dupG variant causes a frameshift starting with codon Valine 1137, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Val1137GlyfsX36. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.3409dupG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the c.3409dupG variant has not been reported previously to our knowledge, other frameshift variants have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Progressive sclerosing poliodystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 19, 2018

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Val1137Glyfs*36) in the POLG gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLG-related disease. ClinVar contains an entry for this variant (Variation ID: 423899). Loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365, 21696159, 27987238). -

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: rs1555452461; hg19: chr15-89861844;