ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1552C>T (p.Arg518Cys) (rs80338686)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790794 SCV000230006 pathogenic not provided 2013-10-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000001975 SCV000711423 pathogenic Biotinidase deficiency 2016-09-02 criteria provided, single submitter clinical testing The p.Arg538Cys variant in BTD has been previously identified in at least 5 comp ound heterozygous and 2 homozygous individuals with severe biotinidase deficienc y and it is the second most common mutation in the biotinidase gene that causes profound biotinidase deficiency in symptomatic children. All these patients had no biotinyl transferase activity in their serum and <10% of mean normal biotiny l-hydrolase activity (Pomponio 1997). This variant has also been identified in 8 /114,620 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs80338686); however, this frequency is low enough to b e consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for biotinidase deficiency in an autoso mal recessive manner based upon case and allelic observations and functional evi dence.
Invitae RCV000001975 SCV000754947 pathogenic Biotinidase deficiency 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 538 of the BTD protein (p.Arg538Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338686, ExAC 0.02%). This variant has been reported as homozygous or in combination with another BTD variant in several individuals affected with biotinidase deficiency (PMID: 9099842, 27657684, 27207447). ClinVar contains an entry for this variant (Variation ID: 1898). 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. A different missense substitution at this codon (p.Arg538Ser) has been determined to be pathogenic (PMID: 22698809, Invitae). This suggests that the arginine residue is critical for BTD protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000001975 SCV000894302 pathogenic Biotinidase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000001975 SCV001194032 pathogenic Biotinidase deficiency 2019-12-19 criteria provided, single submitter clinical testing NM_000060.2(BTD):c.1612C>T(R538C) is classified as pathogenic in the context of biotinidase deficiency. Sources cited for classification include the following: PMID 9099842 and 17185019. Classification of NM_000060.2(BTD):c.1612C>T(R538C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000790794 SCV001470474 pathogenic not provided 2020-08-10 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. 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.
OMIM RCV000001975 SCV000022133 pathogenic Biotinidase deficiency 1997-04-01 no assertion criteria provided literature only
GeneReviews RCV000001975 SCV000040404 pathologic Biotinidase deficiency 2011-03-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Research and Development, ARUP Laboratories RCV000001975 SCV000042698 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only
Natera, Inc. RCV000001975 SCV001461230 pathogenic Biotinidase deficiency 2020-09-16 no assertion criteria provided clinical testing

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