NM_021830.5(TWNK):c.1853C>T (p.Pro618Leu) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 1, 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:: RCV000429667.8

Allele description [Variation Report for NM_021830.5(TWNK):c.1853C>T (p.Pro618Leu)]

NM_021830.5(TWNK):c.1853C>T (p.Pro618Leu)

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.1853C>T (p.Pro618Leu)

Other names:

p.Pro618Leu

HGVS:

NC_000010.11:g.100993308C>T
NG_012624.1:g.10773C>T
NM_001163812.2:c.*148C>T
NM_001163813.2:c.491C>T
NM_001163814.2:c.*148C>T
NM_001368275.1:c.491C>T
NM_021830.3:c.1853C>T
NM_021830.5:c.1853C>TMANE SELECT
NP_001157285.1:p.Pro164Leu
NP_001355204.1:p.Pro164Leu
NP_068602.2:p.Pro618Leu
NC_000010.10:g.102753065C>T
NM_021830.4:c.1853C>T
NR_160738.1:n.2641C>T
NR_160739.1:n.845C>T
NR_160740.1:n.2503C>T
NR_160741.1:n.2459C>T
NR_160742.1:n.2623C>T

Protein change:

P164L

Links:

dbSNP: rs886046632

NCBI 1000 Genomes Browser:

rs886046632

Molecular consequence:

NM_001163812.2:c.*148C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001163814.2:c.*148C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001163813.2:c.491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368275.1:c.491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021830.5:c.1853C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_160738.1:n.2641C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160739.1:n.845C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160740.1:n.2503C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160741.1:n.2459C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160742.1:n.2623C>T - 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
SCV000526374	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 25, 2016)	germline	clinical testing	Citation Link,
SCV002541106	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003439635	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28454995, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000526374

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 25, 2016)

germline

clinical testing

Citation Link,

SCV002541106

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 12, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003439635

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 1, 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield.

Alfares A, Alfadhel M, Wani T, Alsahli S, Alluhaydan I, Al Mutairi F, Alothaim A, Albalwi M, Al Subaie L, Alturki S, Al-Twaijri W, Alrifai M, Al-Rumayya A, Alameer S, Faqeeh E, Alasmari A, Alsamman A, Tashkandia S, Alghamdi A, Alhashem A, Tabarki B, AlShahwan S, et al.

Mol Genet Metab. 2017 Jun;121(2):91-95. doi: 10.1016/j.ymgme.2017.04.002. Epub 2017 Apr 7. No abstract available.

PubMed [citation]

PMID:: 28454995

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000526374.4

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

Description

The P618L variant in the C10orf2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P618L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P618L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P618L as a variant of uncertain significance.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV002541106.1

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439635.2

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

Description

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 298504). This variant is also known as C10orf2 c.1853C>T. This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 28454995). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 618 of the TWNK protein (p.Pro618Leu). 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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