NM_002693.2(POLG):c.830A>T (p.His277Leu) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely 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:
RCV000231645.3

Allele description [Variation Report for NM_002693.2(POLG):c.830A>T (p.His277Leu)]

NM_002693.2(POLG):c.830A>T (p.His277Leu)

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.830A>T (p.His277Leu)
HGVS:
  • NC_000015.10:g.89330106T>A
  • NG_008218.2:g.9690A>T
  • NM_002693.2:c.830A>T
  • NP_002684.1:p.His277Leu
  • LRG_765t1:c.830A>T
  • LRG_765:g.9690A>T
  • LRG_765p1:p.His277Leu
  • NC_000015.9:g.89873337T>A
Protein change:
H277L
Links:
dbSNP: rs138929605
NCBI 1000 Genomes Browser:
rs138929605
Molecular consequence:
  • NM_002693.2:c.830A>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
SCV000287676Invitaecriteria provided, single submitter
Uncertain significance
(May 19, 2017)
germlineclinical testing

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

SCV000886921Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Likely 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

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

Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.

Ashley N, O'Rourke A, Smith C, Adams S, Gowda V, Zeviani M, Brown GK, Fratter C, Poulton J.

Hum Mol Genet. 2008 Aug 15;17(16):2496-506. doi: 10.1093/hmg/ddn150. Epub 2008 May 16. Erratum in: Hum Mol Genet. 2009 Dec 15;18(24):4905-6.

PubMed [citation]
PMID:
18487244
PMCID:
PMC2486441
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000287676.3

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

Description

This sequence change replaces histidine with leucine at codon 277 of the POLG protein (p.His277Leu). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is present in population databases (rs138929605, ExAC 0.07%). This variant has been reported as compound heterozygous in individuals affected with Alpers syndrome (PMID: 18487244), progressive sensory ataxic neuropathy with cerebellar features (PMID: 22357363), and progressive external ophthalmoplegia with parkinsonism (PMID: 21301859). In two of these individuals, this variant was shown to segregate with disease (PMID: 22357363, 21301859). It has also been reported as a single variant in individuals with seizures (PMID: 21880868) as well as unaffected individuals (PMID: 22357363). ClinVar contains an entry for this variant (Variation ID:206583) Experimental studies have shown that introducing this variant at the equivalent amino acid in the yeast POLG protein reduces the protein exonuclease activity (PMID: 22114710, 24508722). However, it has also been shown that the human protein with this variant behaved similarly to wild-type protein in several in vitro assays (PMID: 26095671). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the general population and in affected individuals, but the available evidence is currently insufficient to determine its role 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, SCV000886921.1

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

Description

The NM_002693.2:c.830A>T (NP_002684.1:p.His277Leu) [GRCH38: NC_000015.10:g.89330106T>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18487244 . 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

Last Updated: Apr 17, 2019

Support Center