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 pathogenic Biotinidase deficiency 2021-11-17 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 present in population databases (rs104893686, gnomAD 0.01%). The c.1207T>G (p.Phe403Val) variant frequently co-occurs with the c.1330G>C (p.Asp444His) variant in cis (on the same chromosome), which is known as the c.[1207T>G;1330G>C] haplotype. This haplotype has been reported in the literature in multiple individuals affected with biotinidase deficiency. The c.[1207T>G;1330G>C] haplotype has been observed in homogyzous individual(s) affected with profound biotinidase deficiency (PMID: 10400129, 24525934, 24932929). The c.[1207T>G;1330G>C] haplotype has also been reported to co-occur in trans (on opposite chromosomes) with other pathogenic variant(s) in the BTD gene in individuals affected with biotinidase deficiency (PMID: 25144890, Invitae). The clinical significance of the c.1207T>G variant alone is unclear. 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"). For these reasons, this haplotype has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501861 SCV001748779 likely pathogenic Biotinidase deficiency 2021-06-28 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 in 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 D444H), in multiple individuals affected with Biotinidase Deficiency (e.g. Norrgard_1999, Hesermann_2012, Al Hosani_2014, Haines_2014, Jay_2015, Al-Jasmi_2016). Particularly, the variant was observed in cis with D424H in a few homozygous patients with profound Biotinidase Deficiency (e.g. Norrgard_1999, Hesermann_2012, Al Hosani_2014, Haines_2014). D424H 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 D424H 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 D424H in an individual with no associated disease phenotype. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance/other. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PerkinElmer Genomics RCV000501861 SCV002022095 likely pathogenic Biotinidase deficiency 2021-09-05 no assertion criteria provided clinical testing

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