NM_002693.2(POLG):c.2890C>T (p.Arg964Cys) AND Progressive sclerosing poliodystrophy

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

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000633558.2

Allele description [Variation Report for NM_002693.2(POLG):c.2890C>T (p.Arg964Cys)]

NM_002693.2(POLG):c.2890C>T (p.Arg964Cys)

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.2890C>T (p.Arg964Cys)
Other names:
p.R964C:CGC>TGC
HGVS:
  • NC_000015.10:g.89320857G>A
  • NG_008218.2:g.18939C>T
  • NM_001126131.1:c.2890C>T
  • NM_002693.2:c.2890C>T
  • NP_001119603.1:p.Arg964Cys
  • NP_002684.1:p.Arg964Cys
  • LRG_765t1:c.2890C>T
  • LRG_765:g.18939C>T
  • LRG_765p1:p.Arg964Cys
  • NC_000015.9:g.89864088G>A
Protein change:
R964C
Links:
dbSNP: rs201477273
NCBI 1000 Genomes Browser:
rs201477273
Molecular consequence:
  • NM_002693.2:c.2890C>T - 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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000754804Invitaecriteria provided, single submitter
Uncertain significance
(Jun 17, 2018)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000887118Wong 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

R964C mutation of DNA polymerase gamma imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activity.

Bailey CM, Kasiviswanathan R, Copeland WC, Anderson KS.

Antimicrob Agents Chemother. 2009 Jun;53(6):2610-2. doi: 10.1128/AAC.01659-08. Epub 2009 Apr 13.

PubMed [citation]
PMID:
19364868
PMCID:
PMC2687208

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 (8)

Details of each submission

From Invitae, SCV000754804.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine with cysteine at codon 964 of the POLG protein (p.Arg964Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201477273, ExAC 0.9%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in combination with other POLG variants in individuals affected with progressive external ophthalmoplegia (PEO) and ataxia neuropathy spectrum, and epilepsy (PMID: 24091540, 18546365, 19762913) and as homozygous in an individual affected with lactic acidosis (PMID: 17436221). This variant has also been reported as heterozygous in individuals affected with ataxia, hypotonia, seizure, developmental delay, and PEO (PMID: 21880868, 18546365). ClinVar contains an entry for this variant (Variation ID: 206537). Experimental studies have shown that this missense change has reduced activity in vitro compared to wild-type polymerase gamma (PMID: 17436221, 19364868). 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

From Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicine, SCV000887118.1

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

Description

The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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

Support Center