Total submissions: 4
| 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000021936 | SCV005076304 | pathogenic | Biotinidase deficiency | 2024-04-12 | criteria provided, single submitter | clinical testing | Variant summary: BTD c.[451G>A;1270G>C] (p.[Ala151Thr;Asp424His]) variant, also known as c.[511G>A;1330G>C] (p.[Ala171Thr|Asp444His]), is a complex allele and involves the alteration of multiple nucleotides. The allele frequency of this complex variant could not be determined from large population databases such as gnomAD because the individual variants of the complex have variable frequencies and the exact number of alleles representing a combination of the two in cis is unknown. However, based on the frequency of the least prevalent allele, namely c.451G>A, it can be estimated that the complex variant allele will be found at a frequency not to exceed 0.0003077 in 282712 control chromosomes. This variant frequency is not higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency phenotype (0.0046). c.[451G>A;1270G>C] has been reported in the literature in individuals affected with Biotinidase Deficiency (e.g. Pomponio_2000, Sarafoglou_2009, Borsatto_2019, Tangeraas_2020). Importantly, patients homozygous for this complex variant were all reported with Biotinidase Deficiency and markedly reduced enzyme activity (e.g. Pomponio_2000). These data indicate that the variant may be associated with disease. At least one publication reports this complex variant results in expected activity 0-10% based on the biotinidase activity in plasma (e.g. Borsatto_2019). The following publications have been ascertained in the context of this evaluation (PMID: 10801053, 31337602, 33123633, 19757147). Two ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000021936 | SCV000022135 | pathogenic | Biotinidase deficiency | 2011-01-12 | no assertion criteria provided | literature only |