ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1147T>G (p.Phe383Val)

gnomAD frequency: 0.00002  dbSNP: rs104893686
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000501861 SCV000593788 pathogenic Biotinidase deficiency 2016-04-29 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000727665 SCV000854973 other not provided 2018-08-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000727665 SCV000888006 likely pathogenic not provided 2018-02-05 criteria provided, single submitter clinical testing
Invitae RCV000501861 SCV001212165 uncertain significance Biotinidase deficiency 2021-10-14 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with valine at codon 403 of the BTD protein (p.Phe403Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 10400129, 22698809, 24525934, 26589311). ClinVar contains an entry for this variant (Variation ID: 143949). 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"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501861 SCV001748779 likely pathogenic Biotinidase deficiency 2023-10-12 criteria provided, single submitter clinical testing Variant summary: BTD c.1147T>G (p.Phe383Val), also known as c.1207T>G (p.Phe403Val), results in a non-conservative amino acid change located in the vanin, C-terminal domain (IPR043957) of 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 1.6e-05 in 251384 control chromosomes (gnomAD). c.1147T>G has been reported in the literature, frequently observed in cis with c.1270G>C (p.Asp424His, also known as p.Asp444His), in multiple individuals affected with Biotinidase Deficiency, including several cases where the variant was observed in the homozygous state in cis with p.Asp424His in patients with profound Biotinidase Deficiency (e.g. Norrgard_1999, Hesermann_2012, Al Hosani_2014, Haines_2014, Jay_2015, Al-Jasmi_2016, Khan_2021, Saleh_2021). p.Asp424His is known to be associated with partial Biotinidase deficiency when in compound heterozygosity with other BTD variants associated with a mild or a severe phenotype, while homozygous individuals are expected to be unaffected (as described in ClinVar submission by our laboratory, SCV001363363.2). Given p.Asp424His is linked to partial Biotinidase deficiency, and provided that homozygous patients with [F383V;D424H] showed profound biotinidase deficiency, the variant of interest is implied to have an adverse effect on enzyme function. These data indicate that the variant is likely to be associated with disease. Of interest is a recent report by Hou et al (2020), describing the variant in a compound heterozygosity with p.Asp424His in an individual with no associated disease phenotype. The following publications have been ascertained in the context of this evaluation (PMID: 26589311, 24516753, 24932929, 22698809, 24525934, 31980526, 25144890, 34166817, 10400129, 34374989). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as pathogenic/likely pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000501861 SCV004046224 pathogenic Biotinidase deficiency criteria provided, single submitter clinical testing This variant is also known as c.1270G>C (p.Phe397Val) when using an alternative transcript (NM_001370658.1). The c.1207T>G (p.Phe403Val) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/251384) and is absent in the homozygous state, thus is presumed to be rare. The c.1207T>G (p.Phe403Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as complex allele in conjunction with the p.Asp444His (c.[1207T>G;1330G>C] (p.[Phe403Val;Asp444His]) also known as c.[1147T>G;1270G>C] (p.[Phe383Val;Asp424His])) in patients with biotinidase deficiency and partial biotinidase deficiency (PMID: 10400129, 24525934, 25144890). Functional studies showed that the p.Asp444His variant in conjunction with the p.Phe403Val variant leads to absent biotinidase levels (PMID: 10400129). Based on the available evidence, the c.[1207T>G;1330G>C] complex allele is classified as Pathogenic.

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