NM_002693.2(POLG):c.1276G>A (p.Gly426Ser) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jun 13, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000534104.4

Allele description [Variation Report for NM_002693.2(POLG):c.1276G>A (p.Gly426Ser)]

NM_002693.2(POLG):c.1276G>A (p.Gly426Ser)

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.1276G>A (p.Gly426Ser)
HGVS:
  • NC_000015.10:g.89327324C>T
  • NG_008218.2:g.12472G>A
  • NM_001126131.2:c.1276G>A
  • NM_002693.2:c.1276G>A
  • NP_001119603.1:p.Gly426Ser
  • NP_002684.1:p.Gly426Ser
  • LRG_765t1:c.1276G>A
  • LRG_765:g.12472G>A
  • LRG_765p1:p.Gly426Ser
  • NC_000015.9:g.89870555C>T
Protein change:
G426S
Links:
dbSNP: rs775576189
NCBI 1000 Genomes Browser:
rs775576189
Molecular consequence:
  • NM_001126131.2:c.1276G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.2:c.1276G>A - 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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000630090Invitaecriteria provided, single submitter
Uncertain significance
(Jun 13, 2020)
germlineclinical testing

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

SCV000887142Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Likely pathogenic
(Oct 1, 2018)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

The unfolding clinical spectrum of POLG mutations.

Blok MJ, van den Bosch BJ, Jongen E, Hendrickx A, de Die-Smulders CE, Hoogendijk JE, Brusse E, de Visser M, Poll-The BT, Bierau J, de Coo IF, Smeets HJ.

J Med Genet. 2009 Nov;46(11):776-85. doi: 10.1136/jmg.2009.067686. Epub 2009 Jul 2.

PubMed [citation]
PMID:
19578034

Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.

Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ.

J Med Genet. 2011 Oct;48(10):669-81. doi: 10.1136/jmedgenet-2011-100222. Epub 2011 Aug 31.

PubMed [citation]
PMID:
21880868
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000630090.4

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

Description

This sequence change replaces glycine with serine at codon 426 of the POLG protein (p.Gly426Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs775576189, ExAC 0.002%). This variant has been observed in individual(s) with clinical features of mitochondrial disease (PMID: 19578034, 21880868, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 458687). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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, SCV000887142.1

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

Description

The NM_002693.2:c.1276G>A (NP_002684.1:p.Gly426Ser) [GRCH38: NC_000015.10:g.89327324C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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: Sep 23, 2021

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