NM_002693.3(POLG):c.679C>T (p.Arg227Trp) AND Mitochondrial DNA depletion syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 11, 2024
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:: RCV004586007.1

Allele description [Variation Report for NM_002693.3(POLG):c.679C>T (p.Arg227Trp)]

NM_002693.3(POLG):c.679C>T (p.Arg227Trp)

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.679C>T (p.Arg227Trp)

HGVS:

NC_000015.10:g.89330257G>A
NG_008218.2:g.9539C>T
NM_001126131.2:c.679C>T
NM_002693.3:c.679C>TMANE SELECT
NP_001119603.1:p.Arg227Trp
NP_002684.1:p.Arg227Trp
NP_002684.1:p.Arg227Trp
LRG_765t1:c.679C>T
LRG_765:g.9539C>T
LRG_765p1:p.Arg227Trp
NC_000015.9:g.89873488G>A
NM_002693.2:c.679C>T
P54098:p.Arg227Trp

Protein change:

R227W; ARG227TRP

Links:

UniProtKB: P54098#VAR_023663; OMIM: 174763.0021; dbSNP: rs121918056

NCBI 1000 Genomes Browser:

rs121918056

Molecular consequence:

NM_001126131.2:c.679C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002693.3:c.679C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mitochondrial DNA depletion syndrome
Synonyms:: mitochondrial DNA depletion
Identifiers:: MONDO: MONDO:0018158; MedGen: C0342782; OMIM: PS603041

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005076683	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 11, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28471437, 31694722, 16957900 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005076683

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 11, 2024)

germline

clinical testing

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

Citation Link

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

The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

Hikmat O, Tzoulis C, Chong WK, Chentouf L, Klingenberg C, Fratter C, Carr LJ, Prabhakar P, Kumaraguru N, Gissen P, Cross JH, Jacques TS, Taanman JW, Bindoff LA, Rahman S.

Genet Med. 2017 Nov;19(11):1217-1225. doi: 10.1038/gim.2017.35. Epub 2017 Apr 27. Erratum in: Genet Med. 2019 Apr;21(4):1027. doi: 10.1038/s41436-018-0098-1.

PubMed [citation]

PMID:: 28471437

From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability.

Lindstrand A, Eisfeldt J, Pettersson M, Carvalho CMB, Kvarnung M, Grigelioniene G, Anderlid BM, Bjerin O, Gustavsson P, Hammarsjö A, Georgii-Hemming P, Iwarsson E, Johansson-Soller M, Lagerstedt-Robinson K, Lieden A, Magnusson M, Martin M, Malmgren H, Nordenskjöld M, Norling A, Sahlin E, Stranneheim H, et al.

Genome Med. 2019 Nov 7;11(1):68. doi: 10.1186/s13073-019-0675-1.

PubMed [citation]

PMID:: 31694722
PMCID:: PMC6836550

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005076683.1

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

Description

Variant summary: POLG c.679C>T (p.Arg227Trp) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247648 control chromosomes (gnomAD). c.679C>T has been reported in the literature in multiple individuals affected with features of Mitochondrial DNA Depletion Syndrome - POLG Related (e.g. de Vries_2007, Hikmat_2017, Lindstrand_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28471437, 31694722, 16957900). ClinVar contains an entry for this variant (Variation ID: 13515). Based on the evidence outlined above, the variant was classified as 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

Last Updated: Sep 29, 2024

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