NM_021830.5(TWNK):c.385G>A (p.Val129Met) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 15, 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:: RCV001565369.5

Allele description [Variation Report for NM_021830.5(TWNK):c.385G>A (p.Val129Met)]

NM_021830.5(TWNK):c.385G>A (p.Val129Met)

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.385G>A (p.Val129Met)

HGVS:

NC_000010.11:g.100988595G>A
NG_011646.1:g.3921C>T
NG_012624.1:g.6060G>A
NM_001163812.2:c.385G>A
NM_001163813.2:c.-120+982G>A
NM_001163814.2:c.-120+982G>A
NM_001368275.1:c.-58+982G>A
NM_021830.5:c.385G>AMANE SELECT
NP_001157284.1:p.Val129Met
NP_068602.2:p.Val129Met
NC_000010.10:g.102748352G>A
NM_021830.4:c.385G>A
NR_160738.1:n.1053G>A
NR_160740.1:n.1053G>A
NR_160741.1:n.1053G>A
NR_160742.1:n.1053G>A

Protein change:

V129M

Links:

dbSNP: rs757306944

NCBI 1000 Genomes Browser:

rs757306944

Molecular consequence:

NM_001163813.2:c.-120+982G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001163814.2:c.-120+982G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001368275.1:c.-58+982G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001163812.2:c.385G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021830.5:c.385G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_160738.1:n.1053G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160740.1:n.1053G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160741.1:n.1053G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160742.1:n.1053G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Orchomenella minuta voucher NUN-0075 cytochrome oxidase subunit 1 (COI) gene, partial cds; mitochondrial
gi|1495348670|gnl|uoguelph|CCNUN075 OI-5P|gb|MG311469.1|

Nucleotide
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gi|1497449616|gnl|uoguelph|CCNUN079 OI-5P|gb|MG314439.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001788706	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Aug 28, 2019)	germline	clinical testing	Citation Link,
SCV004685640	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 15, 2023)	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

SCV001788706

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Aug 28, 2019)

germline

clinical testing

Citation Link,

SCV004685640

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 15, 2023)

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

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, SCV001788706.1

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

Description

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function

#	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, SCV004685640.1

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 129 of the TWNK protein (p.Val129Met). This variant is present in population databases (rs757306944, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TWNK-related conditions. ClinVar contains an entry for this variant (Variation ID: 1200366). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TWNK protein function. 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.

#	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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