NM_002693.2(POLG):c.1943C>G (p.Pro648Arg) AND Progressive sclerosing poliodystrophy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 1, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000702972.1

Allele description [Variation Report for NM_002693.2(POLG):c.1943C>G (p.Pro648Arg)]

NM_002693.2(POLG):c.1943C>G (p.Pro648Arg)

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.1943C>G (p.Pro648Arg)
Other names:
p.P648R:CCC>CGC
HGVS:
  • NC_000015.10:g.89325456G>C
  • NG_008218.2:g.14340C>G
  • NM_002693.2:c.1943C>G
  • NP_002684.1:p.Pro648Arg
  • LRG_765t1:c.1943C>G
  • LRG_765:g.14340C>G
  • LRG_765p1:p.Pro648Arg
  • NC_000015.9:g.89868687G>C
  • P54098:p.Pro648Arg
Protein change:
P648R
Links:
UniProtKB: P54098#VAR_058884; dbSNP: rs796052906
NCBI 1000 Genomes Browser:
rs796052906
Molecular consequence:
  • NM_002693.2:c.1943C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000831850Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 15, 2017)
germlineclinical testing

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

SCV000886907Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Oct 1, 2018)
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

Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

Horvath R, Hudson G, Ferrari G, F├╝tterer N, Ahola S, Lamantea E, Prokisch H, Lochm├╝ller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Hanna M, Fialho D, et al.

Brain. 2006 Jul;129(Pt 7):1674-84. Epub 2006 Apr 18.

PubMed [citation]
PMID:
16621917

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000831850.1

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

Description

This sequence change replaces proline with arginine at codon 648 of the POLG protein (p.Pro648Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with autosomal recessive progressive external ophthalmoplegia (PEO) and sensory ataxia, neuropathy, dysarthria, and ophthalmoparesis (SANDO) syndrome (PMID: 16621917, 21550804). ClinVar contains an entry for this variant (Variation ID: 206606). 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#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, SCV000886907.1

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

Description

The NM_002693.2:c.1943C>G (NP_002684.1:p.Pro648Arg) [GRCH38: NC_000015.10:g.89325456G>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21550804 . 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. PS4:Prevalence of variant in affecteds statistically increased over controls. 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: Apr 17, 2019

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