NM_002693.3(POLG):c.855G>C (p.Gln285His) AND Progressive sclerosing poliodystrophy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000758410.6

Allele description [Variation Report for NM_002693.3(POLG):c.855G>C (p.Gln285His)]

NM_002693.3(POLG):c.855G>C (p.Gln285His)

Gene:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.855G>C (p.Gln285His)

Other names:

p.Q285H:CAG>CAC; p.Gln285His

HGVS:

NC_000015.10:g.89330081C>G
NG_008218.2:g.9715G>C
NM_001126131.2:c.855G>C
NM_002693.3:c.855G>CMANE SELECT
NP_001119603.1:p.Gln285His
NP_002684.1:p.Gln285His
NP_002684.1:p.Gln285His
LRG_765t1:c.855G>C
LRG_765:g.9715G>C
LRG_765p1:p.Gln285His
NC_000015.9:g.89873312C>G
NM_002693.2:c.855G>C

Protein change:

Q285H

Links:

dbSNP: rs141367015

NCBI 1000 Genomes Browser:

rs141367015

Molecular consequence:

NM_001126131.2:c.855G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.855G>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

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FAS-associated factor 1 isoform 2 [Mus musculus]
FAS-associated factor 1 isoform 2 [Mus musculus]
gi|2464172844|ref|NP_001405706.1|

Protein
hypothetical protein TR102464 [Schistocephalus solidus]
hypothetical protein TR102464 [Schistocephalus solidus]
gi|974176108|gb|JAP44342.1||gnl|TSA |ssol_TR102464_c0_g1_i1_1

Protein
NADH dehydrogenase subunit 1, partial (mitochondrion) [Schistocephalus solidus]
NADH dehydrogenase subunit 1, partial (mitochondrion) [Schistocephalus solidus]
gi|2747363740|gb|XCA58742.1|

Protein
Miconia psbK-psbI intergenic spacer, partial sequence; chloroplast.
Miconia psbK-psbI intergenic spacer, partial sequence; chloroplast.
PopSet: 732556191

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000887104	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001558371	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000887104

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 1, 2018)

germline

clinical testing

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

SCV001558371

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 21, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (4)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000887104.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The NM_002693.2:c.855G>C (NP_002684.1:p.Gln285His) [GRCH38: NC_000015.10:g.89330081C>G] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001558371.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 285 of the POLG protein (p.Gln285His). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs141367015, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206584). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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