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

Total submissions: 6

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.