ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.581A>G (p.Asn194Ser)

gnomAD frequency: 0.00003  dbSNP: rs397514377
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center RCV000032022 SCV000267236 uncertain significance Biotinidase deficiency 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000520641 SCV000617652 uncertain significance not provided 2020-06-17 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26361991, 15776412)
Labcorp Genetics (formerly Invitae), Labcorp RCV000032022 SCV000834107 pathogenic Biotinidase deficiency 2024-04-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 214 of the BTD protein (p.Asn214Ser). This variant is present in population databases (rs397514377, gnomAD 0.009%). This missense change has been observed in individuals with biotinidase deficiency (PMID: 15776412, 25144890, 29995633; Invitae). ClinVar contains an entry for this variant (Variation ID: 38579). 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%. This variant disrupts the p.Asn214 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 26361991), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000032022 SCV004211423 likely pathogenic Biotinidase deficiency 2023-11-28 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000520641 SCV005187548 uncertain significance not provided criteria provided, single submitter not provided
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000520641 SCV005625381 likely pathogenic not provided 2024-11-22 criteria provided, single submitter clinical testing The BTD c.641A>G (p.Asn214Ser) variant has been reported in the published literature in either a homozygous state or with another pathogenic variant associated with biotinidase deficiency in multiple individuals affected with partial biotinidase deficiency (10-30% of normal BTD activity) (PMID: 25144890 (2015), 26361991 (2015), 29995633 (2018), 33217065 (2021), 35195902 (2022), 38299772 (2024)). This variant has also been reported in a heterozygous state in an individual with approximately 60% of normal BTD enzyme activity (PMID: 38299772 (2024)). The frequency of this variant in the general population, 0.0001 (13/129166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000032022 SCV005660279 likely pathogenic Biotinidase deficiency 2024-03-08 criteria provided, single submitter clinical testing

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