NM_002693.2(POLG):c.2262C>G (p.His754Gln) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: May 4, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000758302.3

Allele description [Variation Report for NM_002693.2(POLG):c.2262C>G (p.His754Gln)]

NM_002693.2(POLG):c.2262C>G (p.His754Gln)

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.2262C>G (p.His754Gln)
HGVS:
  • NC_000015.10:g.89323407G>C
  • NG_008218.2:g.16389C>G
  • NM_001126131.2:c.2262C>G
  • NM_002693.2:c.2262C>G
  • NP_001119603.1:p.His754Gln
  • NP_002684.1:p.His754Gln
  • LRG_765t1:c.2262C>G
  • LRG_765:g.16389C>G
  • LRG_765p1:p.His754Gln
  • NC_000015.9:g.89866638G>C
Protein change:
H754Q
Links:
dbSNP: rs1567188178
NCBI 1000 Genomes Browser:
rs1567188178
Molecular consequence:
  • NM_001126131.2:c.2262C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.2:c.2262C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:
Alpers disease; Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis; Alpers progressive infantile poliodystrophy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008758; MedGen: C0205710; Orphanet: 726; OMIM: 203700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000886957Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Likely pathogenic
(Oct 1, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001390860Invitaecriteria provided, single submitter
Uncertain significance
(May 4, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.

Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ.

J Med Genet. 2011 Oct;48(10):669-81. doi: 10.1136/jmedgenet-2011-100222. Epub 2011 Aug 31.

PubMed [citation]
PMID:
21880868
See all PubMed Citations (3)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000886957.1

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

Description

The NM_002693.2:c.2262C>G (NP_002684.1:p.His754Gln) [GRCH38: NC_000015.10:g.89323407G>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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 Likely Pathogenic.

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

From Invitae, SCV001390860.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces histidine with glutamine at codon 754 of the POLG protein (p.His754Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of POLG-related disease (PMID: 21880868). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 619324). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

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

Last Updated: Mar 14, 2021

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