ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.497G>A (p.Cys166Tyr)

gnomAD frequency: 0.00002  dbSNP: rs397514369
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790752 SCV000230013 likely pathogenic not provided 2012-12-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000021940 SCV000630337 pathogenic Biotinidase deficiency 2024-01-03 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 186 of the BTD protein (p.Cys186Tyr). This variant is present in population databases (rs397514369, gnomAD 0.02%). This missense change has been observed in individual(s) with profound or partial biotinidase deficiency, and suspected BTD deficiency (PMID: 10801053, 22011816, 23644139, 25754625). ClinVar contains an entry for this variant (Variation ID: 25020). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000021940 SCV004039181 pathogenic Biotinidase deficiency 2023-08-23 criteria provided, single submitter clinical testing Variant summary: BTD c.497G>A (p.Cys166Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251430 control chromosomes in the gnomAD database, including 1 homozygote. c.497G>A has been reported in the literature in multiple individuals affected with Biotinidase Deficiency, including a homozygous individual with profound biotinidase deficiency and compound heterozygous cases with other (likely) pathogenic variants (Ben-Rebeh_2012, Ercan_2020, Kasapkara_2015, Pomponio_2000, Thodi_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10801053, 33189081, 22011816, 23644139, 22106832, 25423671). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000021940 SCV004211461 likely pathogenic Biotinidase deficiency 2024-03-20 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000021940 SCV004806122 pathogenic Biotinidase deficiency 2024-03-25 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000021940 SCV004848800 pathogenic Biotinidase deficiency 2022-11-03 criteria provided, single submitter clinical testing The p.Cys186Tyr variant in BTD has been reported in at least 4 compound heterozygous individuals with partial Biotinidase deficiency and reduced Biotinidase activity in their serum (Pomponio 2000 PubMed: 10801053; Ben-Rebeh 2012 PMID: 22106832; Thodi 2013 PMID: 23644139; Al Hosani 2014 PMID: 24932929) and in 15 newborns with Biotinidase deficiency (Karaca 2015 PMID: 25754625; Seker Yilmaz 2018 PMID: 29353266). It was also observed in ClinVar (Variation ID 25020) but absent in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant disrupts a functional cysteine that is likely important for protein function (Karaca 2015 PMID: 25754625). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive partial Biotinidase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PM1_Supporting, PM2_Supporting, PP3, PP4.
Counsyl RCV000021940 SCV001132346 likely pathogenic Biotinidase deficiency 2019-07-11 no assertion criteria provided clinical testing
Natera, Inc. RCV000021940 SCV002081554 pathogenic Biotinidase deficiency 2020-08-06 no assertion criteria provided clinical testing

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