ClinVar Miner

Submissions for variant NM_021830.5(TWNK):c.1609T>C (p.Tyr537His) (rs144001072)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726623 SCV000523428 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing The Y537H variant in the TWNK gene has been reported in the heterozygous state in single adult female with progressive ptosis, ophthalmoplegia, lower limb weakness, myopathic signs on EMG, severely reduced COX activity and multiple mtDNA deletions in muscle with ragged red fibers; while not present in her father or siblings, a maternal sample was not available for complete familial segregation (Ronchi et al., 2011). The Y537H variant is observed in 38/126,722 (0.03%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The Y537H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726623 SCV000701817 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001105997 SCV001263021 benign Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV001105999 SCV001263023 benign Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 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 Clinical Services Laboratory,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.

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