ClinVar Miner

Submissions for variant NM_021830.5(TWNK):c.1070G>C (p.Arg357Pro) (rs758026634)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779014 SCV000915455 likely pathogenic Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3 2017-10-09 criteria provided, single submitter clinical testing The C10orf2 (TWNK) gene is one of at least 10 genes in which variants are known to cause progressive external ophthalmoplegia (PEO) with mitochondrial DNA deletions. The c.1070G>C (p.Arg357Pro) missense variant has been reported in at least three studies in which it is found in a heterozygous state in 12 individuals from three families with features of PEO (Rivera et al. 2007; Fratter et al. 2010; Paradas et al. 2013). A majority of these individuals presented with a late-onset form of the disorder and showed mild ocular phenotypes reported as ophthalmoparesis or ptosis; however, two individuals (ages 61 and 73 years) did not have ptosis and were considered neurologically typical. Assessment of mitochondrial DNA deletions was not specified in these individuals, and only one affected individual reported non-ocular myopathy including proximal limb weakness. The p.Arg357Pro variant was absent from 150 controls (Rivera et al. 2007). This variant is reported at a frequency of 0.000115 in the African population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. An in vitro functional study in E. coli demonstrated that the variant retained its helicase function, exhibited high DNA binding affinity, and normal nucleotide hydrolysis and thermal stability (Longley et al. 2010). Based on the evidence, the p.Arg357Pro variant is classified as likely pathogenic for a mild presentation of progressive external ophthalmoplegia with mitochondrial DNA deletions. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV001102837 SCV001259529 uncertain significance Infantile onset spinocerebellar ataxia 2017-09-15 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 RCV001102838 SCV001259530 uncertain significance Autosomal recessive cerebellar ataxia 2017-09-15 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 RCV001102839 SCV001259531 uncertain significance Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 2017-09-15 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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