rs1555453538

Positions:

• chr15-89326677-CA-C

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.1646del​(p.Leu549CysfsTer4) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L549L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLG NM_002693.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.01

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 15-89326677-CA-C is Pathogenic according to our data. Variant chr15-89326677-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449949.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.1646del	p.Leu549CysfsTer4	frameshift_variant	9/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*918del		3_prime_UTR_variant	9/23
POLG	NM_001126131.2	c.1646del	p.Leu549CysfsTer4	frameshift_variant	9/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1646del	p.Leu549CysfsTer4	frameshift_variant	9/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Aug 03, 2017

This 10 year old male has a history of autism spectrum disorder, epilepsy, growth hormone deficiency, hypothyroidism, and ADHD combined type. Patient has had multiple EEGs that reportedly showed centrotemporal spikes that were considered epileptiform, though no seizures have been noted. He has reportedly had two normal MRIs. He is heterozygous for a nonsense POLG variant (c.1646delT) that was paternally inherited. His 45 year old father is reportedly healthy and is in a physically rigorous profession. A second variant, including a deletion or duplication of one or more exons, has not been excluded in this patient. This variant is absent from gnomAD and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, whole exome sequencing also identified another de novo variant of uncertain significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2017

The c.1646delT variant in the POLG gene has not been reported previously as a pathogenic variantnor as a benign variant, to our knowledge. The c.1646delT variant causes a frameshift starting withcodon Leucine 549, changes this amino acid to a Cysteine residue, and creates a premature Stop codonat position 4 of the new reading frame, denoted p.Leu549CysfsX4. This variant is predicted to causeloss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.The c.1646delT variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). We interpret c.1646delT as a likely pathogenicvariant. -

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: rs1555453538; hg19: chr15-89869908;