NM_002693.2(POLG):c.3218C>T (p.Pro1073Leu)

NM_002693.2(POLG):c.3218C>T (p.Pro1073Leu)

Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
  • Chr15:89862217 (on Assembly GRCh37)
  • Chr15:89318986 (on Assembly GRCh38)
Protein change:
P1073L
HGVS:
  • NG_008218.1:g.20810C>T
  • NM_002693.2:c.3218C>T
  • NC_000015.10:g.89318986G>A (GRCh38)
  • NC_000015.9:g.89862217G>A (GRCh37)
  • NP_002684.1:p.Pro1073Leu
Links:
NCBI 1000 Genomes Browser:
rs267606959
Molecular consequence:
NM_002693.2:c.3218C>T: missense variant [Sequence Ontology SO:0001583]

Clinical significance

NM_002693.2(POLG):c.3218C>T (p.Pro1073Leu)

Clinical significance:
Pathogenic/Likely pathogenic
Review status:
2 stars out of maximum of 4 stars
classified by multiple submitters
Number of submission(s):
2
Condition(s)
See supporting ClinVar records

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Recent Activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter
(Last submitted)
Submission accession
Pathogenic
(Oct 25, 2013)
classified by single submitter
(literature only)
literature onlygermlinePubMed (1)
OMIM
(Dec 30, 2010)
SCV000034721
Pathogenic
(Oct 25, 2013)
classified by single submitter
(literature only)
literature onlygermlinePubMed (1)
OMIM
(Dec 30, 2010)
SCV000034722

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermlinenot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

Kurt et al. (2010) identified a 3218C-T transition in exon 20 of the POLG gene, resulting in a pro1073-to-leu (P1073L) substitution, in compound heterozygosity with another pathogenic POLG mutation in 4 patients who all had a hepatocerebral disorder with psychomotor delay, seizures, and liver disease, consistent with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome. The P1073L mutation occurred in a conserved residue in the polymerase domain of the protein. An unrelated girl and boy were compound heterozygous for the P1073L and A467T (174763.0002) mutations. Both had developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility, reminiscent of the allelic disorder MNGIE syndrome (MTDPS4B; 613662). Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. RT-PCR showed severe mtDNA depletion in liver tissue (72.1% depletion compared to controls). The boy had status epilepticus with coma, cholestasis, optic atrophy, hyperplastic gastropathy with gastric ulcer, and death at age 3 years, 4 months. In addition, 2 boys were compound heterozygous for the P1073L and W748S (174763.0013) and G848S (174763.0006) mutations, respectively. The first child had severe attention-deficit/hyperactivity disorder with motor and verbal tics, status epilepticus with coma and myoclonus, liver dysfunction, and cavitation in the cerebrum, thalamus, cerebellum, and basal ganglia. He died at age 13 years. The other child had poor growth, hypotonia, seizures, and intestinal hypomotility and died at age 10 months. Muscle tissue showed mtDNA depletion (64%). Kurt et al. (2010) emphasized the phenotypic variability associated with POLG mutations, and noted that various signs and symptoms can occur in each associated disorder. Three of the children with the P1073L mutation also had gastrointestinal dysmotility, suggesting that this mutation may be associated with that particular feature.

Last Updated: Oct 30, 2014

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