NM_021830.5(TWNK):c.1462_1463del (p.Phe488fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 22, 2024
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:: RCV000198764.6

Allele description [Variation Report for NM_021830.5(TWNK):c.1462_1463del (p.Phe488fs)]

NM_021830.5(TWNK):c.1462_1463del (p.Phe488fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

10q24.31

Genomic location:

Preferred name:

NM_021830.5(TWNK):c.1462_1463del (p.Phe488fs)

HGVS:

NC_000010.11:g.100989862_100989863del
NG_011646.1:g.2654_2655del
NG_012624.1:g.7327_7328del
NM_001163812.2:c.1462_1463del
NM_001163813.2:c.100_101del
NM_001163814.2:c.100_101del
NM_001368275.1:c.100_101del
NM_021830.4:c.1462_1463del
NM_021830.5:c.1462_1463delMANE SELECT
NP_001157284.1:p.Phe488fs
NP_001157285.1:p.Phe34fs
NP_001157286.1:p.Phe34fs
NP_001355204.1:p.Phe34fs
NP_068602.2:p.Phe488fs
NC_000010.10:g.102749618_102749619del
NC_000010.10:g.102749619_102749620del
NM_021830.4:c.1462_1463delTT
NR_160738.1:n.2130_2131del
NR_160739.1:n.290_291del
NR_160740.1:n.2068_2069del
NR_160741.1:n.2068_2069del
NR_160742.1:n.2068_2069del
p.F488PfsX21

Protein change:

F34fs

Links:

dbSNP: rs863223925

NCBI 1000 Genomes Browser:

rs863223925

Molecular consequence:

NM_001163812.2:c.1462_1463del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001163813.2:c.100_101del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001163814.2:c.100_101del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368275.1:c.100_101del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_021830.5:c.1462_1463del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_160738.1:n.2130_2131del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160739.1:n.290_291del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160740.1:n.2068_2069del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160741.1:n.2068_2069del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160742.1:n.2068_2069del - 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
SCV000251225	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 22, 2024)	germline	clinical testing	Citation Link,
SCV002246441	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 2, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26633542, 21681116, 27551684, 31455392, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251225

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 22, 2024)

germline

clinical testing

Citation Link,

SCV002246441

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 2, 2021)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical application of whole-exome sequencing across clinical indications.

Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, Vertino-Bell A, Smaoui N, Neidich J, Monaghan KG, McKnight D, Bai R, Suchy S, Friedman B, Tahiliani J, Pineda-Alvarez D, Richard G, Brandt T, Haverfield E, Chung WK, Bale S.

Genet Med. 2016 Jul;18(7):696-704. doi: 10.1038/gim.2015.148. Epub 2015 Dec 3.

PubMed [citation]

PMID:: 26633542

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

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000251225.4

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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; This variant is associated with the following publications: (PMID: 26633542)

#	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, SCV002246441.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 214190). This premature translational stop signal has been observed in individual(s) with abnormality of the nervous system (PMID: 26633542). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Phe488Profs*21) 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

Last Updated: Oct 8, 2024

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