ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.581A>G (p.Asn194Ser) (rs397514377)

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Total submissions: 4
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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 2017-08-01 criteria provided, single submitter clinical testing The N214S variant has previously been reported in association with profound biotinidase deficiency in an individual who was heterozygous for N214S and D444H on one allele (in cis) and another pathogenic variant in trans (Wolf et al., 2005). The N214S variant is observed in 6/66,740 (0.01%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The N214S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (Y210C, R211C , L215F, Y216N, E218D) have been reported in the Human Gene Mutation Database in association with biotinidase deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000032022 SCV000834107 uncertain significance Biotinidase deficiency 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 214 of the BTD protein (p.Asn214Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs397514377, ExAC 0.009%). This variant has been observed in an individual affected with partial biotinidase deficiency (PMID: 25144890). ClinVar contains an entry for this variant (Variation ID: 25030, 38579). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Asn214Thr) in affected individuals suggests that this may be a clinically significant residue (PMID: 26361991). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Research and Development, ARUP Laboratories RCV000032022 SCV000055349 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only Previously published as seen with D444H, now seen alone

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