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NM_021830.5(TWNK):c.1453T>A (p.Phe485Ile) AND not provided

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 20, 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:
RCV003680381.2

Allele description [Variation Report for NM_021830.5(TWNK):c.1453T>A (p.Phe485Ile)]

NM_021830.5(TWNK):c.1453T>A (p.Phe485Ile)

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.1453T>A (p.Phe485Ile)
HGVS:
  • NC_000010.11:g.100989853T>A
  • NG_011646.1:g.2663A>T
  • NG_012624.1:g.7318T>A
  • NM_001163812.2:c.1453T>A
  • NM_001163813.2:c.91T>A
  • NM_001163814.2:c.91T>A
  • NM_001368275.1:c.91T>A
  • NM_021830.5:c.1453T>AMANE SELECT
  • NP_001157284.1:p.Phe485Ile
  • NP_001157285.1:p.Phe31Ile
  • NP_001157286.1:p.Phe31Ile
  • NP_001355204.1:p.Phe31Ile
  • NP_068602.2:p.Phe485Ile
  • NP_068602.2:p.Phe485Ile
  • NC_000010.10:g.102749610T>A
  • NM_021830.3:c.1453T>A
  • NR_160738.1:n.2121T>A
  • NR_160739.1:n.281T>A
  • NR_160740.1:n.2059T>A
  • NR_160741.1:n.2059T>A
  • NR_160742.1:n.2059T>A
Protein change:
F31I
Molecular consequence:
  • NM_001163812.2:c.1453T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001163813.2:c.91T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001163814.2:c.91T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368275.1:c.91T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021830.5:c.1453T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_160738.1:n.2121T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160739.1:n.281T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160740.1:n.2059T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160741.1:n.2059T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_160742.1:n.2059T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004411101Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 20, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Two families with autosomal dominant progressive external ophthalmoplegia.

Kiechl S, Horváth R, Luoma P, Kiechl-Kohlendorfer U, Wallacher-Scholz B, Stucka R, Thaler C, Wanschitz J, Suomalainen A, Jaksch M, Willeit J.

J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1125-8.

PubMed [citation]
PMID:
15258213
PMCID:
PMC1739155

Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity.

Longley MJ, Humble MM, Sharief FS, Copeland WC.

J Biol Chem. 2010 Sep 24;285(39):29690-702. doi: 10.1074/jbc.M110.151795. Epub 2010 Jul 20.

PubMed [citation]
PMID:
20659899
PMCID:
PMC2943296
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004411101.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 485 of the TWNK protein (p.Phe485Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical feature of autosomal dominant TWNK-related conditions (Invitae). 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 expected to disrupt TWNK protein function with a positive predictive value of 95%. This variant disrupts the p.Phe485 amino acid residue in TWNK. Other variant(s) that disrupt this residue have been observed in individuals with TWNK-related conditions (PMID: 15258213, 20659899), which suggests that this may be a clinically significant amino acid residue. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024