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

dbSNP: rs758026634

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779014	SCV000915455	likely pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001102839	SCV001259531	uncertain significance	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	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.
CeGaT Center for Human Genetics Tuebingen	RCV003222127	SCV003916632	likely pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	TWNK: PM1, PM2, PP3, PS4:Supporting
Athena Diagnostics	RCV003222127	SCV004229831	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with autosomal dominant PEO. This variant associates with disease in multiple families, at least one of which is reported to exhibit reduced penetrance. Computational tools predict that this variant is damaging.