ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.683T>C (p.Ile228Thr) (rs397514382)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Research and Development, ARUP Laboratories RCV000021960 SCV000042629 pathogenic Biotinidase deficiency 2017-02-17 criteria provided, single submitter clinical testing Enzyme activity @ < 0.4 U/L with a paired control in the normal range. Seen with c.528G>T,p.K176N.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000021960 SCV000602896 likely pathogenic Biotinidase deficiency 2019-05-23 criteria provided, single submitter clinical testing The BTD c.743T>C; p.Ile248Thr variant (rs397514382) is reported in the literature in at least one individual affected with biotinidase deficiency who carried a second, pathogenic variant in BTD (Cowan 2012). This variant is reported in ClinVar (Variation ID: 25037), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 248 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Cowan TM et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug;106(4):485-7.
Counsyl RCV000021960 SCV000800591 uncertain significance Biotinidase deficiency 2017-11-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284605 SCV001470475 likely pathogenic not provided 2019-10-31 criteria provided, single submitter clinical testing Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae RCV000021960 SCV001585143 pathogenic Biotinidase deficiency 2020-03-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 248 of the BTD protein (p.Ile248Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs397514382, ExAC 0.009%). This variant has been observed in combination with another BTD variant in an individual affected with biotinidase deficiency (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 25037). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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