ClinVar Miner

Submissions for variant NM_001195248.2(APTX):c.18G>T (p.Trp6Cys) (rs144076460)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200146 SCV000251157 likely pathogenic not provided 2014-07-01 criteria provided, single submitter clinical testing p.Trp6Cys (TGG>TGT): c.18 G>T in exon 3 of the APTX gene (NM_175073.2). The W6C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The W6C 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 conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000357224 SCV000479644 uncertain significance Ataxia-oculomotor apraxia type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000274167 SCV000479645 uncertain significance Ataxia with Oculomotor Apraxia 2016-06-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000200146 SCV000705962 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000200146 SCV000883415 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing The APTX: c.18G>T; p.Trp6Cys variant (rs144076460; ClinVar Variation ID: 214126) has been previously reported in a cohort of patients with a clinical diagnosis of oculomotor apraxia type 1 (van Minkelen 2015). However, no other specific genotype or inheritance information was provided, and the authors considered this variant to be of uncertain clinical significance. This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish European populations of 0.1% (identified in 122 out of 126,606 chromosomes, including 1 homozygote). The tryptophan at codon 6 is highly conserved considering 12 species up to Baker’s yeast (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on APTX protein structure/function (SIFT: damaging and PolyPhen2: probably damaging). However, based on the available information, the clinical significance of the p.Trp6Cys variant cannot be determined with certainty.

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