ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.565C>T (p.Arg189Cys) (rs369102875)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000537387 SCV000788646 uncertain significance Biotinidase deficiency 2017-10-05 criteria provided, single submitter clinical testing
Invitae RCV000537387 SCV000630339 uncertain significance Biotinidase deficiency 2018-02-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 209 of the BTD protein (p.Arg209Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs369102875, ExAC 0.01%). This variant has been reported in the literature in one individual affected with partial biotinidase deficiency co-occurring with a pathogenic variant in this gene (PMID: 26810761) and in an individual with abnormal newborn screening who also carried a pathogenic variant (Invitae). ClinVar contains an entry for this variant (Variation ID: 458809). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Arg209His) has been determined to be likely pathogenic (PMID: 24797656). This suggests that the arginine residue is critical for BTD protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been observed in affected individuals and it is located in a residue important for protein function. However, the evidence is not enough to make a definite classification and more genetic and/or functional data are needed. For these reasons, it has been classified as a Variant of Uncertain Significance.
Research and Development, ARUP Laboratories RCV000537387 SCV000845807 pathogenic Biotinidase deficiency 2017-02-17 criteria provided, single submitter clinical testing Enzyme activity @ 2.1 U/L. Seen with c.1368A>C,p.Q456H.

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