NM_002693.2(POLG):c.2243G>C (p.Trp748Ser) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(3);Uncertain significance(1) (Last evaluated: Oct 1, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000014461.22

Allele description [Variation Report for NM_002693.2(POLG):c.2243G>C (p.Trp748Ser)]

NM_002693.2(POLG):c.2243G>C (p.Trp748Ser)

Gene:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.2(POLG):c.2243G>C (p.Trp748Ser)
Other names:
p.W748S:TGG>TCG; NM_001126131.1(POLG):c.2243G>C(p.Trp748Ser); NM_002693.2(POLG):c.2243G>C(p.Trp748Ser)
HGVS:
  • NC_000015.10:g.89323426C>G
  • NG_008218.2:g.16370G>C
  • NM_001126131.1:c.2243G>C
  • NM_002693.2:c.2243G>C
  • NP_001119603.1:p.Trp748Ser
  • NP_002684.1:p.Trp748Ser
  • LRG_765t1:c.2243G>C
  • LRG_765:g.16370G>C
  • LRG_765p1:p.Trp748Ser
  • NC_000015.9:g.89866657C>G
  • NG_008218.1:g.16370G>C
  • P54098:p.Trp748Ser
Protein change:
W748S; TRP748SER
Links:
UniProtKB: P54098#VAR_023673; OMIM: 174763.0013; dbSNP: rs113994097
NCBI 1000 Genomes Browser:
rs113994097
Molecular consequence:
  • NM_002693.2:c.2243G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
10

Condition(s)

Name:
Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:
Alpers Syndrome; Mitochondrial DNA depletion syndrome 4A (Alpers type); Alpers-Huttenlocher Syndrome
Identifiers:
MedGen: C0205710; Orphanet: 726; OMIM: 203700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000034712OMIMno assertion criteria providedPathogenic
(Dec 1, 2007)
germlineliterature only

PubMed (8)
[See all records that cite these PMIDs]

SCV000331432EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Feb 2, 2016)
germlineclinical testing

Citation Link,

SCV000630126Invitaecriteria provided, single submitter
Uncertain significance
(May 15, 2018)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV000887113Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Oct 1, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknown10not providednot providednot providednot providedclinical testing

Citations

PubMed

Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family.

Rantamäki M, Krahe R, Paetau A, Cormand B, Mononen I, Udd B.

Neurology. 2001 Sep 25;57(6):1043-9.

PubMed [citation]
PMID:
11571332

Do carriers of POLG mutation W748S have disease manifestations?

Rantamäki M, Luoma P, Virta JJ, Rinne JO, Paetau A, Suomalainen A, Udd B.

Clin Genet. 2007 Dec;72(6):532-7. Epub 2007 Sep 25.

PubMed [citation]
PMID:
17894835
See all PubMed Citations (20)

Details of each submission

From OMIM, SCV000034712.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (8)

Description

In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in the POLG gene, resulting in a trp748-to-ser (W748S) substitution. The mutated residue lies within a highly conserved block of 6 amino acids that form a beta-sheet in the spacer, or linker, region of the enzyme and is presumed to be involved in primer-template interaction of the DNA polymerase. An unrelated Finnish patient had the same homozygous mutation, and an unrelated British patient was compound heterozygous for W748S and A467T (174763.0002). In addition to the W748S mutation, all 5 patients carried a 3428A-G transition, resulting in a glu1143-to-gly (E1143G) substitution on the same allele. W748S was not identified in 168 Belgian and 70 Finnish controls; E1143G was identified in 11 Belgian and 3 Finnish controls. Van Goethem et al. (2004) concluded that E1143G is a low-frequency polymorphism that forms a common ancestral haplotype; however, they noted that the contribution of E1143G to the phenotype was unclear.

In a follow-up report of the family reported by Rantamaki et al. (2001) and Van Goethem et al. (2004), Rantamaki et al. (2007) found that heterozygous W748S carriers showed no clinically manifesting phenotype. Presumably unrelated neurologic signs and symptoms, including dementia, epilepsy, and migraine, were found in several carriers, but clearly defined neurologic diseases did not segregate with the mutation. The only notable finding was a subclinical axonal sensory neuropathy in the majority of carriers.

Hakonen et al. (2005) found that the POLG allele with W748S and E1143G in cis is among the most common genetic causes of inherited ataxia in Finland. They identified 27 patients with mitochondrial recessive ataxia syndrome from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, they examined the haplotypes of 13 non-Finnish European patients with the W748S mutation. Haplotype analysis demonstrated that all the chromosomes carrying these 2 changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common Northern haplotypes outside the core haplotype could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicated that this form of ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes.

Winterthun et al. (2005) identified a homozygous W748S mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). Both patients were also homozygous for another putative disease-causing POLG mutation (Q497H; 174763.0016).

In 4 children with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: W748S and G848S (174763.0006). All patients died in childhood. Nguyen et al. (2005) reported a patient with Alpers syndrome who was compound heterozygous for G848S and W748S.

Hakonen et al. (2007) demonstrated that the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype, but differed from Belgian and British patients, suggesting that the founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. Hakonen et al. (2007) estimated that the common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000331432.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided10not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided10not providednot providednot provided

From Invitae, SCV000630126.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces tryptophan with serine at codon 748 of the POLG protein (p.Trp748Ser). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs113994097, ExAC 0.6%). This variant has been reported in families and individuals affected with POLG-related conditions in the homozygous or compound heterozygous states, or heterozygous without a second reported variant (PMID: 15477547, 20438629, 26755490, 26942291, 23212759, 26607151, 25713120, 22931735). This variant commonly occurs on the same chromosome (in cis) with p.Gln497His and/or p.Glu1143Gly, so it is unclear if this particular variant contributes to disease. ClinVar contains entries for this variant (Variation ID: 13507, 157526). Experimental studies do not agree on whether this variant affects protein function (PMID: 17088268, 20153822). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicine, SCV000887113.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The NM_002693.2:c.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. 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. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 17, 2019

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