NM_002693.2(POLG):c.2246T>C (p.Phe749Ser) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(2);Uncertain significance(1) (Last evaluated: Jul 8, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000758416.6

Allele description [Variation Report for NM_002693.2(POLG):c.2246T>C (p.Phe749Ser)]

NM_002693.2(POLG):c.2246T>C (p.Phe749Ser)

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.2246T>C (p.Phe749Ser)
Other names:
p.F749S:TTT>TCT
HGVS:
  • NC_000015.10:g.89323423A>G
  • NG_008218.2:g.16373T>C
  • NM_001126131.2:c.2246T>C
  • NM_002693.2:c.2246T>C
  • NP_001119603.1:p.Phe749Ser
  • NP_002684.1:p.Phe749Ser
  • LRG_765t1:c.2246T>C
  • LRG_765:g.16373T>C
  • LRG_765p1:p.Phe749Ser
  • NC_000015.9:g.89866654A>G
Protein change:
F749S
Links:
dbSNP: rs202037973
NCBI 1000 Genomes Browser:
rs202037973
Molecular consequence:
  • NM_001126131.2:c.2246T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.2:c.2246T>C - 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

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
SCV000887114Wong 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]

SCV000956727Invitaecriteria provided, single submitter
Uncertain significance
(Jul 8, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001139680Mendelicscriteria provided, single submitter
Pathogenic
(May 28, 2019)
unknownclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot 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

Novel POLG splice site mutation and optic atrophy.

Milone M, Wang J, Liewluck T, Chen LC, Leavitt JA, Wong LJ.

Arch Neurol. 2011 Jun;68(6):806-11. doi: 10.1001/archneurol.2011.124. Erratum in: Arch Neurol. 2011 Aug;68(8):1084. Arch Neurol. 2011 Nov;68(11):1446.

PubMed [citation]
PMID:
21670405
See all PubMed Citations (6)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000887114.1

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

Description

The NM_002693.2:c.2246T>C (NP_002684.1:p.Phe749Ser) [GRCH38: NC_000015.10:g.89323423A>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16545482 ; 21880868 . 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. 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

From Invitae, SCV000956727.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces phenylalanine with serine at codon 749 of the POLG protein (p.Phe749Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs202037973, ExAC 0.07%). This variant has been observed in in combination with other POLG variants in individuals affected with autosomal recessive progressive external ophthalmoplegia, Alpers syndrome, or seizures (PMID: 21670405, 16545482, 21880868, 18716558). ClinVar contains an entry for this variant (Variation ID: 206520). 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

From Mendelics, SCV001139680.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 17, 2021

Support Center