ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.451G>A (p.Ala151Thr) (rs13073139)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000078073 SCV000238743 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing The A171T variant has only been reported on the same allele as D444H comprising what has been described as a double mutation allele, denoted A171T;D444H. A171T;D444H has been observed in approximately 17% of alleles in children with profound biotinidase deficiency ascertained by newborn screening in the United States (Norrgard et al., 1999). The A171T variant was seen with the D444H variant at GeneDx.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078073 SCV000281607 pathogenic not provided 2014-08-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000031859 SCV000611183 pathogenic Biotinidase deficiency 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000031859 SCV000630334 uncertain significance Biotinidase deficiency 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 171 of the BTD protein (p.Ala171Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs13073139, ExAC 0.07%). This variant has been reported in the literature in multiple individuals affected with biotinidase (BTD) deficiency co-occurring on the same chromosome with the common pathogenic p.Asp444His BTD variant (PMID: 10206677, 21752405, 9654207, 20556795, 12227467, 25174816, 20549359, 27329734, 9375914). ClinVar contains an entry for this variant (Variation ID: 25016, 38298). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078073 SCV000888019 pathogenic not provided 2015-11-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031859 SCV000915026 pathogenic Biotinidase deficiency 2018-03-30 criteria provided, single submitter clinical testing Across a selection of the available literature, the BTD c.511G>A (p.Ala171Thr) variant has been found as part of a complex allele [p.Ala171Thr;p.Asp444His] in a majority of cases including 25 individuals, a majority of whom were newborns, with the variant in a compound heterozygous state, 20 with profound biotinidase deficiency, four with partial biotinidase deficiency, and one individual who did not have information on biotinidase activity (Norrgard et al. 1998; Norrgard et al. 1999; Borsatto et al. 2014; Borsatto et al. 2017). The second variant identified in the compound heterozygous individuals was most often a missense variant. The complex allele has also been reported in a homozygous state in three individuals with profound biotinidase deficiency including a father-daughter pair from a consanguineous family where one parent and two grandparents were all heterozygous carriers of the variant and were unaffected (Wolf et al. 1997). A study by Lindau-Shepart et al. (2012) also identified the p.Ala171Thr variant in at least ten patients without the p.Asp444His variant, including five with a different second variant, but in whom zygosity was not specified. In addition, since a limited number of variants were evaluated in this study, the authors suggest that a less common variant may also be present with the p.Ala171Thr variant in the five individuals with a single variant detected. The p.Ala171Thr variant was absent from 376 normal blood spots and is reported at a frequency of 0.00066 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Ala171Thr variant is classified as pathogenic for biotinidase deficiency.
Mendelics RCV000031859 SCV001136341 pathogenic Biotinidase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000031859 SCV001193777 pathogenic Biotinidase deficiency 2019-12-26 criteria provided, single submitter clinical testing NM_000060.2(BTD):c.511G>A(A171T) is classified as pathogenic in the context of biotinidase deficiency. Please note that this variant is frequently observed in combination with D444H in the literature, which suggests they are likely to be on the same chromosome. When A171T and D444H are present on the same chromosome, this combination of variants is associated with profound biotinidase deficiency. Sources cited for classification include the following: PMID 27625817, 29995633, 28971021, 21752405 and 18845537. Classification of NM_000060.2(BTD):c.511G>A(A171T) 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078073 SCV001246039 pathogenic not provided 2018-12-01 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000031859 SCV001448938 pathogenic Biotinidase deficiency 2018-09-13 criteria provided, single submitter clinical testing
GeneReviews RCV000031859 SCV000054465 pathologic Biotinidase deficiency 2011-03-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Research and Development, ARUP Laboratories RCV000031859 SCV000845804 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000031859 SCV001423159 not provided Biotinidase deficiency no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 12-12-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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