NM_002693.2(POLG):c.1760C>T (p.Pro587Leu) 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:
RCV000408293.4

Allele description [Variation Report for NM_002693.2(POLG):c.1760C>T (p.Pro587Leu)]

NM_002693.2(POLG):c.1760C>T (p.Pro587Leu)

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.1760C>T (p.Pro587Leu)
HGVS:
  • NC_000015.10:g.89325639G>A
  • NG_008218.2:g.14157C>T
  • NM_001126131.1:c.1760C>T
  • NM_002693.2:c.1760C>T
  • NP_001119603.1:p.Pro587Leu
  • NP_002684.1:p.Pro587Leu
  • LRG_765t1:c.1760C>T
  • LRG_765:g.14157C>T
  • LRG_765p1:p.Pro587Leu
  • NC_000015.9:g.89868870G>A
  • NG_008218.1:g.14157C>T
  • P54098:p.Pro587Leu
Protein change:
P587L; PRO587LEU
Links:
UniProtKB: P54098#VAR_023671; OMIM: 174763.0011; dbSNP: rs113994096
NCBI 1000 Genomes Browser:
rs113994096
Molecular consequence:
  • NM_002693.2:c.1760C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
15

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
SCV000331604EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Feb 10, 2016)
germlineclinical testing

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

Citation Link,

SCV000536728Division of Human Genetics,Children's Hospital of Philadelphia - CSER-PediSeqno assertion criteria providedPathogenic
(Dec 12, 2016)
maternalresearch

PubMed (4)
[See all records that cite these PMIDs]

SCV000543885Invitaecriteria provided, single submitter
Uncertain significance
(May 14, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000886904Wong 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 providedgermlineunknown15not providednot providednot providednot providedclinical testing
not providedmaternalyesnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.

Van Goor F, Yu H, Burton B, Hoffman BJ.

J Cyst Fibros. 2014 Jan;13(1):29-36. doi: 10.1016/j.jcf.2013.06.008. Epub 2013 Jul 23.

PubMed [citation]
PMID:
23891399

The development of next-generation sequencing assays for the mitochondrial genome and 108 nuclear genes associated with mitochondrial disorders.

Dames S, Chou LS, Xiao Y, Wayman T, Stocks J, Singleton M, Eilbeck K, Mao R.

J Mol Diagn. 2013 Jul;15(4):526-34. doi: 10.1016/j.jmoldx.2013.03.005. Epub 2013 May 9.

PubMed [citation]
PMID:
23665194
See all PubMed Citations (10)

Details of each submission

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000331604.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided15not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided15not providednot providednot provided

From Division of Human Genetics,Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536728.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000543885.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces proline with leucine at codon 587 of the POLG protein (p.Pro587Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases, including a homozygous individual (rs113994096, ExAC 0.3%). This variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it was observed on the same chromosome (in cis) with a second (p.Thr251Ile) variant (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868). In many of these cases, these two variants in cis were observed on the opposite chromosome (in trans) from a pathogenic variant in an affected individual. These findings are consistent with autosomal recessive inheritance, and suggest that one or both of these variants contribute to disease. Furthermore, these two variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879). ClinVar contains an entry for this variant (Variation ID:13505). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare variant that is almost always observed in cis with a second variant. It has been shown to segregate with disease, and has also been observed in many individuals with sporadic disease. However, it has also been observed in unaffected individuals, and in the population databases. Furthermore, because it almost always occurs in cis with p.Thr251Ile, the individual contribution of this variant to disease cannot be disambiguated. For these reasons, this change 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, SCV000886904.1

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

Description

The NM_002693.2:c.1760C>T (NP_002684.1:p.Pro587Leu) [GRCH38: NC_000015.10:g.89325639G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 ; 12825077 . 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. 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 Pathogenic.

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

Last Updated: Mar 30, 2019

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