VCV000383137.25 - ClinVar

NM_021830.5(TWNK):c.1609T>C (p.Tyr537His)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(2)

10 out of 10 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021830.5(TWNK):c.1609T>C (p.Tyr537His)

Variation ID: 383137 Accession: VCV000383137.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q24.31 10: 100990885 (GRCh38) [ NCBI UCSC ] 10: 102750642 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Oct 12, 2025	Sep 23, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_021830.5:c.1609T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068602.2:p.Tyr537His	missense
NM_001163812.2:c.1609T>C	NP_001157284.1:p.Tyr537His	missense
NM_001163813.2:c.247T>C	NP_001157285.1:p.Tyr83His	missense
NM_001163814.2:c.247T>C	NP_001157286.1:p.Tyr83His	missense
NM_001368275.1:c.247T>C	NP_001355204.1:p.Tyr83His	missense
NR_160738.1:n.2397T>C		non-coding transcript variant
NR_160739.1:n.557T>C		non-coding transcript variant
NR_160740.1:n.2215T>C		non-coding transcript variant
NR_160741.1:n.2215T>C		non-coding transcript variant
NR_160742.1:n.2335T>C		non-coding transcript variant
NC_000010.11:g.100990885T>C
NC_000010.10:g.102750642T>C
NG_011646.1:g.1631A>G
NG_012624.1:g.8350T>C

... more HGVS ... less HGVS

Protein change

Y537H, Y83H

Other names

Canonical SPDI

NC_000010.11:100990884:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

The Genome Aggregation Database (gnomAD), exomes 0.00039

Exome Aggregation Consortium (ExAC) 0.00013

The Genome Aggregation Database (gnomAD), exomes 0.00015

The Genome Aggregation Database (gnomAD) 0.00020

The Genome Aggregation Database (gnomAD) 0.00021

Trans-Omics for Precision Medicine (TOPMed) 0.00024

Links

ClinGen: CA5653294 dbSNP: rs144001072 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TWNK		-	-	GRCh38 GRCh37	618	637

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV001105997.4
Autosomal recessive cerebellar ataxia	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2017	RCV001105998.4
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	Benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV001105999.4
Hereditary spastic paraplegia	Uncertain significance (1)	criteria provided, single submitter	Sep 30, 2020	RCV001848766.3
TWNK-related disorder	Uncertain significance (1)	criteria provided, single submitter	Sep 3, 2023	RCV004533016.1
Infantile onset spinocerebellar ataxia	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2017	RCV001106000.4
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Sep 23, 2025	RCV000726623.16
not specified	Uncertain significance (1)	criteria provided, single submitter	Feb 7, 2024	RCV003993959.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3	Illumina Laboratory Services, Illumina Accession: SCV001263021.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 21689831 Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Autosomal recessive cerebellar ataxia	Illumina Laboratory Services, Illumina Accession: SCV001263022.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome	Illumina Laboratory Services, Illumina Accession: SCV001263023.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Infantile onset spinocerebellar ataxia	Illumina Laboratory Services, Illumina Accession: SCV001263024.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Sep 30, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary spastic paraplegia	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002106278.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Sep 03, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	TWNK-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004113941.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: show The TWNK c.1609T>C variant is predicted to result in the amino acid substitution p.Tyr537His. This variant was reported in the heterozygous state in individuals with chronic external ophthalmoplegia or Parkinson's disease; however, pathogenicity was not established (Ronchi et al. 2011. PubMed ID: 21689831; Percetti et al. 2022. PubMed ID: 35792653). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-102750642-T-C), which may be too frequent to be a primary cause of autosomal dominant disease. Although we suspect TWNK c.1609T>C (p.Tyr537His) may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jan 06, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002295990.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 16, 2025	Publications: PubMed (1) PubMed: 21689831 Comment: show This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 537 of the TWNK protein (p.Tyr537His). This variant is present in population databases (rs144001072, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of TWNK-related conditions (PMID: 21689831). ClinVar contains an entry for this variant (Variation ID: 383137). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TWNK protein function with a negative predictive value of 80%. 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Oct 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000701817.3 First in ClinVar: Dec 19, 2017 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TWNK Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed

Uncertain significance (Feb 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004813212.2 First in ClinVar: Apr 15, 2024 Last updated: May 25, 2025	Publications: PubMed (1) PubMed: 21689831 Comment: show Variant summary: TWNK c.1609T>C (p.Tyr537His) results in a conservative amino acid change located in the DNA helicase, DnaB-like, C-terminal (IPR007694) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 1614126 control chromosomes in the gnomAD database (v4.0.0), including 1 homozygotes c.1609T>C has been reported in the literature in individuals affected with Opthalmoplegia (Ronchi_2011). This report does not provide unequivocal conclusions about association of the variant with Infantile Onset Spinocerebellar Ataxia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21689831). ClinVar contains an entry for this variant (Variation ID: 383137). Based on the evidence outlined above, the variant was classified as uncertain significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Sep 23, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV000523428.7 First in ClinVar: Mar 08, 2017 Last updated: Oct 12, 2025	Comment: show In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26615986, 35792653, 21689831) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The TWNK c.1609T>C variant is predicted to result in the amino acid substitution p.Tyr537His. This variant was reported in the heterozygous state in individuals with chronic external ophthalmoplegia or Parkinson's disease; however, pathogenicity was not established (Ronchi et al. 2011. PubMed ID: 21689831; Percetti et al. 2022. PubMed ID: 35792653). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-102750642-T-C), which may be too frequent to be a primary cause of autosomal dominant disease. Although we suspect TWNK c.1609T>C (p.Tyr537His) may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 537 of the TWNK protein (p.Tyr537His). This variant is present in population databases (rs144001072, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of TWNK-related conditions (PMID: 21689831). ClinVar contains an entry for this variant (Variation ID: 383137). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TWNK protein function with a negative predictive value of 80%. 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.

Comment:

Variant summary: TWNK c.1609T>C (p.Tyr537His) results in a conservative amino acid change located in the DNA helicase, DnaB-like, C-terminal (IPR007694) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 1614126 control chromosomes in the gnomAD database (v4.0.0), including 1 homozygotes c.1609T>C has been reported in the literature in individuals affected with Opthalmoplegia (Ronchi_2011). This report does not provide unequivocal conclusions about association of the variant with Infantile Onset Spinocerebellar Ataxia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21689831). ClinVar contains an entry for this variant (Variation ID: 383137). Based on the evidence outlined above, the variant was classified as uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Two novel mutations in PEO1 (twinkle) gene associated with chronic external ophthalmoplegia.	Ronchi D	Journal of the neurological sciences	2011	PMID: 21689831
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TWNK	-	-	-	-

Text-mined citations for rs144001072 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 12, 2025

ClinVar Genomic variation as it relates to human health

NM_021830.5(TWNK):c.1609T>C (p.Tyr537His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs144001072 ...