NM_002693.3(POLG):c.3383G>A (p.Arg1128His) AND Progressive sclerosing poliodystrophy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 7, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000758473.10

Allele description [Variation Report for NM_002693.3(POLG):c.3383G>A (p.Arg1128His)]

NM_002693.3(POLG):c.3383G>A (p.Arg1128His)

Genes:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
POLGARF:POLG alternative reading frame [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.3383G>A (p.Arg1128His)

HGVS:

NC_000015.10:g.89318640C>T
NG_008218.2:g.21156G>A
NG_011736.1:g.79678C>T
NM_001126131.2:c.3383G>A
NM_002693.3:c.3383G>AMANE SELECT
NP_001119603.1:p.Arg1128His
NP_002684.1:p.Arg1128His
NP_002684.1:p.Arg1128His
LRG_765t1:c.3383G>A
LRG_500:g.79678C>T
LRG_765:g.21156G>A
LRG_765p1:p.Arg1128His
NC_000015.9:g.89861871C>T
NM_002693.2:c.3383G>A

Protein change:

R1128H

Links:

dbSNP: rs1405268319

NCBI 1000 Genomes Browser:

rs1405268319

Molecular consequence:

NM_001126131.2:c.3383G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.3383G>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

Recent activity

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M-phase inducer phosphatase 2 isoform X1 [Pongo abelii]
M-phase inducer phosphatase 2 isoform X1 [Pongo abelii]
gi|686761514|ref|XP_009231674.1|

Protein
Influenza A virus (A/mallard/Netherlands/2/2005(H4N2)) segment 1, complete seque...
Influenza A virus (A/mallard/Netherlands/2/2005(H4N2)) segment 1, complete sequence
gi|238821914|gnl|NIGSP|NIGSP-CEIRS- 7-RF-00018.PB2|gb|CY041257.1|

Nucleotide
Rattus norvegicus amylase 2a3 (Amy2a3), mRNA
Rattus norvegicus amylase 2a3 (Amy2a3), mRNA
gi|1937369514|ref|NM_031502.2|

Nucleotide
DA428479 COLON2 Homo sapiens cDNA clone COLON2004231 5', mRNA sequence
DA428479 COLON2 Homo sapiens cDNA clone COLON2004231 5', mRNA sequence
gi|80826604|gnl|dbEST|33282841|dbj| 479.1|

Nucleotide
PFS2 Homeodomain-like superfamily protein [Arabidopsis thaliana]
PFS2 Homeodomain-like superfamily protein [Arabidopsis thaliana]
Gene ID:814678

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000887186	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001545289	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 7, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18546365, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000887186

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 1, 2018)

germline

clinical testing

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

SCV001545289

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 7, 2022)

germline

clinical testing

PubMed (2)
[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

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 (3)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV000887186.1

#	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.3383G>A (NP_002684.1:p.Arg1128His) [GRCH38: NC_000015.10:g.89318640C>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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic.

#	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 Invitae, SCV001545289.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1128 of the POLG protein (p.Arg1128His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365). ClinVar contains an entry for this variant (Variation ID: 593423). 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. 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: Aug 4, 2024

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