Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000400305 | SCV000361367 | uncertain significance | Cutaneous porphyria | 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. |
| Invitae | RCV001357032 | SCV002224407 | uncertain significance | not provided | 2021-10-22 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 299192). This variant has not been reported in the literature in individuals affected with UROS-related conditions. This variant is present in population databases (rs369561042, ExAC 0.01%). This sequence change replaces lysine with asparagine at codon 109 of the UROS protein (p.Lys109Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. |
| Department of Pathology and Laboratory Medicine, |
RCV001357032 | SCV001552357 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The UROS p.Lys109Asn variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs369561042) and ClinVar (classified as a VUS by Illumina). The variant was also identified in control databases in 14 of 282664 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7210 chromosomes (freq: 0.000139), European (non-Finnish) in 12 of 129050 chromosomes (freq: 0.000093) and East Asian in 1 of 19954 chromosomes (freq: 0.00005), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish) or South Asian populations. The p.Lys109 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. |