Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000664856 | SCV000788877 | uncertain significance | Biotinidase deficiency | 2017-01-11 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000664856 | SCV002779295 | uncertain significance | Biotinidase deficiency | 2022-04-04 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000664856 | SCV003251393 | uncertain significance | Biotinidase deficiency | 2022-06-06 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 480 of the BTD protein (p.Gly480Glu). This variant is present in population databases (rs558477960, gnomAD 0.007%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 27329734). ClinVar contains an entry for this variant (Variation ID: 550185). 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. This variant disrupts the p.Gly480 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25754625). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001355022 | SCV001549779 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The BTD p.Gly482Glu variant was identified in 1 of 122 proband chromosomes (frequency: 0.0082) from individuals or families with biotinidase deficiency (Wiltink_2016_PMID:27329734). The variant was identified in dbSNP (ID: rs558477960), ClinVar (classified as a VUS by Counsyl) and LOVD 3.0 (classified as likely benign) but was not identified in Cosmic. The variant was also identified in control databases in 11 of 251444 chromosomes at a frequency of 0.000044 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 8 of 113722 chromosomes (freq: 0.00007), Latino in 2 of 34592 chromosomes (freq: 0.000058) and East Asian in 1 of 18394 chromosomes (freq: 0.000054), while the variant was not observed in the African, Ashkenazi Jewish, European (Finnish), Other, and South Asian populations. The p.Gly482 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 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. |