ClinVar Miner

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

gnomAD frequency: 0.00021  dbSNP: rs144001072
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726623 SCV000523428 uncertain significance not provided 2024-05-01 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26615986, 35792653, 21689831)
Eurofins Ntd Llc (ga) RCV000726623 SCV000701817 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001105997 SCV001263021 benign Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV001105998 SCV001263022 uncertain significance Autosomal recessive cerebellar ataxia 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV001105999 SCV001263023 benign Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Laboratory Services, Illumina RCV001106000 SCV001263024 uncertain significance Infantile onset spinocerebellar ataxia 2017-04-28 criteria provided, single submitter clinical testing 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001848766 SCV002106278 uncertain significance Hereditary spastic paraplegia 2020-09-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000726623 SCV002295990 uncertain significance not provided 2024-01-23 criteria provided, single submitter clinical testing 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). 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 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.
PreventionGenetics, part of Exact Sciences RCV004533016 SCV004113941 uncertain significance TWNK-related disorder 2023-09-03 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003993959 SCV004813212 uncertain significance not specified 2024-02-07 criteria provided, single submitter clinical testing 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.

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