Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000346256 | SCV000404696 | uncertain significance | Renal tubular dysgenesis | 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, 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 | RCV001354798 | SCV002303463 | uncertain significance | not provided | 2022-07-12 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1036 of the ACE protein (p.Asn1036Lys). This variant is present in population databases (rs142947404, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ACE-related conditions. ClinVar contains an entry for this variant (Variation ID: 324414). 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. 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. |
| Fulgent Genetics, |
RCV002504099 | SCV002815138 | uncertain significance | Microvascular complications of diabetes, susceptibility to, 3; Hemorrhage, intracerebral, susceptibility to; Renal tubular dysgenesis of genetic origin | 2022-05-26 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001354798 | SCV001549499 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ACE p.Asn462Lys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs142947404) and in ClinVar (classified as a VUS by Illumina). The variant was also identified in control databases in 211 of 281706 chromosomes at a frequency of 0.000749 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 14 of 7202 chromosomes (freq: 0.001944), Ashkenazi Jewish in 20 of 10340 chromosomes (freq: 0.001934), European (non-Finnish) in 123 of 128168 chromosomes (freq: 0.00096), South Asian in 29 of 30598 chromosomes (freq: 0.000948), Latino in 23 of 35382 chromosomes (freq: 0.00065) and European (Finnish) in 2 of 25102 chromosomes (freq: 0.00008); it was not observed in the African and East Asian populations. The p.Asn462 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) 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. |