ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.409C>T (p.Arg137Cys)

gnomAD frequency: 0.00001  dbSNP: rs397514363
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414201 SCV000491032 likely pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing The R157C variant in the BTD gene has been reported previously in association with partial biotinidase deficiency when present in the homozygous state or when in trans with another disease-causing variant (Milánkovics et al., 2007; Ohlsson et al., 2010). The R157C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R157C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (T152P, T152R, R157H, C160Y, A162V) 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. The R157C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp RCV000021931 SCV001580649 pathogenic Biotinidase deficiency 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 157 of the BTD protein (p.Arg157Cys). This variant is present in population databases (rs397514363, gnomAD 0.007%). This missense change has been observed in individuals with biotinidase deficiency (PMID: 17185019, 20224900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 25012). 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.Arg157 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9396567, 11313766, 20224900, 22698809). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000021931 SCV004211446 likely pathogenic Biotinidase deficiency 2024-02-08 criteria provided, single submitter clinical testing
Counsyl RCV000021931 SCV001132345 uncertain significance Biotinidase deficiency 2019-05-07 no assertion criteria provided clinical testing

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