NM_021830.5(TWNK):c.341T>G (p.Met114Arg) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 22, 2022
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:: RCV001763002.8

Allele description [Variation Report for NM_021830.5(TWNK):c.341T>G (p.Met114Arg)]

NM_021830.5(TWNK):c.341T>G (p.Met114Arg)

Gene:

TWNK:twinkle mtDNA helicase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q24.31

Genomic location:

Preferred name:

NM_021830.5(TWNK):c.341T>G (p.Met114Arg)

HGVS:

NC_000010.11:g.100988551T>G
NG_011646.1:g.3965A>C
NG_012624.1:g.6016T>G
NM_001163812.2:c.341T>G
NM_001163813.2:c.-120+938T>G
NM_001163814.2:c.-120+938T>G
NM_001368275.1:c.-58+938T>G
NM_021830.5:c.341T>GMANE SELECT
NP_001157284.1:p.Met114Arg
NP_068602.2:p.Met114Arg
NC_000010.10:g.102748308T>G
NM_021830.4:c.341T>G
NR_160738.1:n.1009T>G
NR_160740.1:n.1009T>G
NR_160741.1:n.1009T>G
NR_160742.1:n.1009T>G

Protein change:

M114R

Links:

dbSNP: rs765038479

NCBI 1000 Genomes Browser:

rs765038479

Molecular consequence:

NM_001163813.2:c.-120+938T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001163814.2:c.-120+938T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001368275.1:c.-58+938T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001163812.2:c.341T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_021830.5:c.341T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_160738.1:n.1009T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160740.1:n.1009T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160741.1:n.1009T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160742.1:n.1009T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001989059	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 15, 2020)	germline	clinical testing	Citation Link,
SCV002136192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27822509, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001989059

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 15, 2020)

germline

clinical testing

Citation Link,

SCV002136192

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 22, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Peripheral neuropathy in patients with CPEO associated with single and multiple mtDNA deletions.

Lehmann D, Kornhuber ME, Clajus C, Alston CL, Wienke A, Deschauer M, Taylor RW, Zierz S.

Neurol Genet. 2016 Dec;2(6):e113.

PubMed [citation]

PMID:: 27822509
PMCID:: PMC5089902

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV001989059.2

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

Description

Identified with another variant in TWNK (phase unknkown) in an individual with chronic progressive external ophthalmoplegia (Lehmann et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27822509)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002136192.3

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

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TWNK protein function. ClinVar contains an entry for this variant (Variation ID: 1303544). This missense change has been observed in individual(s) with progressive external ophthalmoplegia with mitochondrial DNA deletions (PMID: 27822509). This variant is present in population databases (rs765038479, gnomAD 0.007%). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 114 of the TWNK protein (p.Met114Arg).

#	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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