ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001975 SCV000486491 pathogenic Biotinidase deficiency 2016-06-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790794 SCV000230006 pathogenic not provided 2013-10-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000001975 SCV000894302 pathogenic Biotinidase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000001975 SCV000040404 pathologic Biotinidase deficiency 2011-03-15 no assertion criteria provided curation Converted during submission to Pathogenic.
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.
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; 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.
OMIM RCV000001975 SCV000022133 pathogenic Biotinidase deficiency 1997-04-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000001975 SCV000042698 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only

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