ClinVar Miner

Submissions for variant NM_002658.5(PLAU):c.878G>A (p.Arg293Gln) (rs546931331)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000308085 SCV000364886 benign Quebec platelet disorder 2018-01-12 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355163 SCV001549959 uncertain significance not provided no assertion criteria provided clinical testing The PLAU p.Arg207Gln variant was not identified in the literature but was identified in dbSNP (ID: rs546931331) and ClinVar (classified as likely benign by Illumina for Quebec platelet disorder). The variant was identified in control databases in 57 of 280872 chromosomes at a frequency of 0.0002029 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 33 of 30612 chromosomes (freq: 0.001078), European (non-Finnish) in 20 of 127256 chromosomes (freq: 0.000157), Other in 1 of 7214 chromosomes (freq: 0.000139), African in 1 of 24960 chromosomes (freq: 0.00004), European (Finnish) in 1 of 25112 chromosomes (freq: 0.00004) and Latino in 1 of 35406 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg207 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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