rs1554887097

Positions:

• chr10-100989331-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_021830.5(TWNK):​c.1121G>A​(p.Arg374Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TWNK NM_021830.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.95

Genes affected

TWNK (HGNC:1160): (twinkle mtDNA helicase) This gene encodes a hexameric DNA helicase which unwinds short stretches of double-stranded DNA in the 5' to 3' direction and, along with mitochondrial single-stranded DNA binding protein and mtDNA polymerase gamma, is thought to play a key role in mtDNA replication. The protein localizes to the mitochondrial matrix and mitochondrial nucleoids. Mutations in this gene cause infantile onset spinocerebellar ataxia (IOSCA) and progressive external ophthalmoplegia (PEO) and are also associated with several mitochondrial depletion syndromes. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_021830.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-100989330-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 10-100989331-G-A is Pathogenic according to our data. Variant chr10-100989331-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989331-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TWNK	NM_021830.5	c.1121G>A	p.Arg374Gln	missense_variant	1/5	ENST00000311916.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWNK	ENST00000311916.8	c.1121G>A	p.Arg374Gln	missense_variant	1/5	1	NM_021830.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2021	Published functional studies in HEK293 cells demonstrate a damaging effect with a reduction of enzyme activity to 25% compared to wild-type (Goffart et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); Located within the linker region of the TWINKLE helicase protein, a region reported to be important for hexamerization and helicase activity (Korhonen et al., 2008) This variant is associated with the following publications: (PMID: 31147703, 26838077, 26979109, 22353293, 20880070, 20479361, 17620490, 16639411, 29264394, 18279890, 20659899, 18971204, 17272269, 20417176, 11431692) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 374 of the TWNK protein (p.Arg374Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant progressive external ophthalmoplegia (PMID: 11431692, 20880070, 32161153). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426106). 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. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Apr 07, 2017

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 16, 2024

Variant summary: TWNK c.1121G>A (p.Arg374Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251374 control chromosomes. c.1121G>A has been reported in the literature in multiple individuals affected with Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Dominant 3 and the variant segregated with the disease (example: Baloh_20017, Hou_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that the variant changes the normal function of the protein (Matsushima_2016, Goffart_2009). The following publications have been ascertained in the context of this evaluation (PMID: 17620490, 17272269, 35289132, 18971204). ClinVar contains an entry for this variant (Variation ID: 426106). Based on the evidence outlined above, the variant was classified as pathogenic. -

Depression;C0162674:Progressive external ophthalmoplegia;C0452138:Bilateral sensorineural hearing impairment;C1527344:Dysphonia;C1865916:Bilateral ptosis;C4021546:Abnormal mitochondria in muscle tissue;C4021726:EMG: myopathic abnormalities;C4025729:Neuromuscular dysphagia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.85		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		1.0
MPC		1.4
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.54
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554887097; hg19: chr10-102749088;