NM_002693.2(POLG):c.3383G>A (p.Arg1128His) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 3, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000758473.2

Allele description [Variation Report for NM_002693.2(POLG):c.3383G>A (p.Arg1128His)]

NM_002693.2(POLG):c.3383G>A (p.Arg1128His)

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.3383G>A (p.Arg1128His)
HGVS:
  • NC_000015.10:g.89318640C>T
  • NG_008218.2:g.21156G>A
  • NG_011736.1:g.79678C>T
  • NM_001126131.2:c.3383G>A
  • NM_002693.2:c.3383G>A
  • NP_001119603.1:p.Arg1128His
  • NP_002684.1:p.Arg1128His
  • LRG_765t1:c.3383G>A
  • LRG_500:g.79678C>T
  • LRG_765:g.21156G>A
  • LRG_765p1:p.Arg1128His
  • NC_000015.9:g.89861871C>T
Protein change:
R1128H
Links:
dbSNP: rs1405268319
NCBI 1000 Genomes Browser:
rs1405268319
Molecular consequence:
  • NM_001126131.2:c.3383G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.2:c.3383G>A - 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
SCV000887186Wong 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]

SCV001545289Invitaecriteria provided, single submitter
Uncertain significance
(Oct 3, 2020)
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

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, Milone M, Cohen BH, Wical B, Ganesh J, Basinger AA, Burton BK, Swoboda K, Gilbert DL, Vanderver A, Saneto RP, Maranda B, Arnold G, Abdenur JE, Waters PJ, Copeland WC.

Hum Mutat. 2008 Sep;29(9):E150-72. doi: 10.1002/humu.20824.

PubMed [citation]
PMID:
18546365
PMCID:
PMC2891192
See all PubMed Citations (3)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000887186.1

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

Description

The NM_002693.2:c.3383G>A (NP_002684.1:p.Arg1128His) [GRCH38: NC_000015.10:g.89318640C>T] 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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. PP5:Reputable source(s) suggest that the variant is pathogenic. 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, SCV001545289.1

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

Description

This sequence change replaces arginine with histidine at codon 1128 of the POLG protein (p.Arg1128His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. 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 conditions (PMID: 18546365). ClinVar contains an entry for this variant (Variation ID: 593423). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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

Last Updated: Aug 27, 2021

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