ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1301A>G (p.Tyr434Cys) (rs397514345)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524591 SCV000630327 likely pathogenic Biotinidase deficiency 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 454 of the BTD protein (p.Tyr454Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs397514345, ExAC 0.2%). This variant has been reported to co-occur with other BTD variants in individuals affected with profound BTD deficiency (PMID: 15776412, 26810761) and has been observed to segregate with disease in a family with biotinidase deficiency (Invitae). The variant has also been shown on the opposite chromosome (in trans) from a pathogenic variant in an individual with abnormal biotinidase enzyme testing (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 458806). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000524591 SCV000796970 uncertain significance Biotinidase deficiency 2018-01-05 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000524591 SCV000845830 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only Seen in haplotype with c.235C>T
GeneDx RCV001578266 SCV001805821 uncertain significance not provided 2021-08-12 no assertion criteria provided clinical testing Reported in one individual with profound biotinidase deficiency in whom two known pathogenic variants in the BTD gene were also found. In this individual, the Y454C variant was in cis with one of the known pathogenic variants with the other pathogenic variant on the opposite allele (Wolf et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 30616616, 26810761, 15776412, 31973013)

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