NM_002693.3(POLG):c.3716del (p.Pro1239fs) AND Progressive sclerosing poliodystrophy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 30, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000633555.8

Allele description [Variation Report for NM_002693.3(POLG):c.3716del (p.Pro1239fs)]

NM_002693.3(POLG):c.3716del (p.Pro1239fs)

Genes:

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
FANCI:FA complementation group I [Gene - OMIM - HGNC]
POLGARF:POLG alternative reading frame [Gene - HGNC]

Variant type:

Deletion

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_002693.3(POLG):c.3716del (p.Pro1239fs)

HGVS:

NC_000015.10:g.89316756del
NC_000015.9:g.89859986del
NG_008218.2:g.23041del
NG_011736.1:g.77794del
NM_001113378.2:c.*297delMANE SELECT
NM_001126131.2:c.3716del
NM_001376910.1:c.*297del
NM_001376911.1:c.*297del
NM_002693.3:c.3716delMANE SELECT
NM_018193.3:c.*297del
NP_001119603.1:p.Pro1239fs
NP_002684.1:p.Pro1239fs
NP_002684.1:p.Pro1239fs
LRG_765t1:c.3716del
LRG_500:g.77794del
LRG_765:g.23041del
LRG_765p1:p.Pro1239fs
NC_000015.9:g.89859986del
NC_000015.9:g.89859986delG
NC_000015.9:g.89859987del
NM_002693.2:c.3716del
NM_002693.2:c.3716delC

Protein change:

P1239fs

Links:

dbSNP: rs1555452076

NCBI 1000 Genomes Browser:

rs1555452076

Molecular consequence:

NM_001113378.2:c.*297del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001376910.1:c.*297del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001376911.1:c.*297del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_018193.3:c.*297del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126131.2:c.3716del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002693.3:c.3716del - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000754801	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 30, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000754801

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 30, 2019)

germline

clinical testing

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

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

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. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000754801.6

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

Description

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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the extended amino acids is currently unknown. This variant has not been reported in the literature in individuals with POLG-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the POLG gene (p.Pro1239Hisfs*54). While this is not anticipated to result in nonsense mediated decay, it is expected to extend the POLG protein by 53 amino acids.

#	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: Feb 20, 2024

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