NM_021830.5(TWNK):c.967C>T (p.Arg323Ter) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 31, 2023
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:: RCV000198844.9

Allele description

NM_021830.5(TWNK):c.967C>T (p.Arg323Ter)

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.967C>T (p.Arg323Ter)

Other names:

p.R323*:CGA>TGA

HGVS:

NC_000010.11:g.100989177C>T
NG_011646.1:g.3339G>A
NG_012624.1:g.6642C>T
NM_001163812.2:c.967C>T
NM_001163813.2:c.-119-467C>T
NM_001163814.2:c.-119-467C>T
NM_001368275.1:c.-57-529C>T
NM_021830.5:c.967C>TMANE SELECT
NP_001157284.1:p.Arg323Ter
NP_068602.2:p.Arg323Ter
NC_000010.10:g.102748934C>T
NM_021830.4:c.967C>T
NR_160738.1:n.1635C>T
NR_160740.1:n.1635C>T
NR_160741.1:n.1635C>T
NR_160742.1:n.1635C>T

Protein change:

R323*

Links:

dbSNP: rs863223919

NCBI 1000 Genomes Browser:

rs863223919

Molecular consequence:

NM_001163813.2:c.-119-467C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001163814.2:c.-119-467C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001368275.1:c.-57-529C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_160738.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160740.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160741.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160742.1:n.1635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001163812.2:c.967C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_021830.5:c.967C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000251217	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 14, 2020)	germline	clinical testing	Citation Link,
SCV003008015	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21681116, 27551684, 31455392, 28492532
SCV003813051	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 26, 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

SCV000251217

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 14, 2020)

germline

clinical testing

Citation Link,

SCV003008015

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 31, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003813051

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 26, 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	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

Next-generation sequencing facilitates the diagnosis in a child with twinkle mutations causing cholestatic liver failure.

Goh V, Helbling D, Biank V, Jarzembowski J, Dimmock D.

J Pediatr Gastroenterol Nutr. 2012 Feb;54(2):291-4. doi: 10.1097/MPG.0b013e318227e53c. No abstract available.

PubMed [citation]

PMID:: 21681116

Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease.

Pierce SB, Gulsuner S, Stapleton GA, Walsh T, Lee MK, Mandell JB, Morales A, Klevit RE, King MC, Rogers RC.

Cold Spring Harb Mol Case Stud. 2016 Jul;2(4):a001107. doi: 10.1101/mcs.a001107.

PubMed [citation]

PMID:: 27551684
PMCID:: PMC4990813

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000251217.14

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

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge

#	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 Invitae, SCV003008015.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 214183). This variant has not been reported in the literature in individuals affected with TWNK-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg323*) in the TWNK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TWNK are known to be pathogenic (PMID: 21681116, 27551684, 31455392).

#	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 Revvity Omics, Revvity, SCV003813051.2

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

#	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: Jul 7, 2024

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