Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000021936 | SCV000711610 | pathogenic | Biotinidase deficiency | 2017-01-31 | criteria provided, single submitter | clinical testing | The p.[Ala171Thr;Asp444His] (NM_000060.2 c.[511G>A;1330G>C]) allele in BTD has p reviously been reported in several compound heterozygous individuals with biotin idase deficiency (Norrgard 1998 and Borsatto 2014). While the frequency of the c ombined allele in the general population is not documented, the p.Ala171Thr vari ant has only been reported in individuals who carried the more common partial de ficiency p.Asp444His variant, suggesting that these two variants may always occu r on the same chromosome and the frequency of the combined allele may be the sam e as the reported frequency of the p.Ala171Thr variant alone in the population (47/120,592 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs13073139)); however, this cannot be conclusively d etermined. In summary, the p.[Ala171Thr;Asp444His] allele meets our criteria to be classified as pathogenic for biotinidase deficiency in an autosomal recessive manner primarily based upon its occurrence in trans with other pathogenic varia nts in affected individuals. Although the p.Asp444His variant on its own has par tial activity, the p.[Ala171Thr;Asp444His] combined allele is thought to represe nt a more severe effect. |
| Johns Hopkins Genomics, |
RCV000021936 | SCV001762382 | pathogenic | Biotinidase deficiency | 2021-06-21 | criteria provided, single submitter | clinical testing | c.[451G>A;1270G>C] is a complex allele containing two BTD variants (rs13073139; rs13078881) that are located on the same chromosome (in cis). Each variant has an entry in ClinVar. c.451G>A is rare (<0.1%) in a large population dataset (gnomAD: 87/282712 total alleles, 0.03%, no homozygotes), while c.1207G>C is polymorphic (3.19%) in most ancestral populations. This allele is a common cause of profound bioitinidase deficiency (less than 10% mean normal activity in serum) when it occurs in a compound heterozygous state (in trans) with another pathogenic BTD variant. It accounts for approximately 17% of BTD variants in children with profound biotinidase deficiency identified by newborn screening in the United States. This allele was detected in the patient’s father and was absent in the patient’s mother confirming that these two variants are on the same chromosome. We consider this complex allele, which combines c.451G>A and c.1207G>C, to be pathogenic. |
| OMIM | RCV000021936 | SCV000022135 | pathogenic | Biotinidase deficiency | 2011-01-12 | no assertion criteria provided | literature only |