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

gnomAD frequency: 0.00002  dbSNP: rs104893686

Total submissions: 6

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	2023-04-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00012 (4/34590 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has only been reported as a complex allele associated with profound biotinidase deficiency in homozygous individuals or those with another profound deficiency allele affected with paraparesis, optic neuropathy, and speech delay (PMIDs: 22698809 (2012), 24525934 (2014), 24932929 (2014), 26589311 (2015), 33016994 (2020), 34374989 (2021)). The complex allele with just c.1330G>C (p.Asp444His) on the other allele resulted in partial biotinidase deficiency (PMID: 25144890 (2015)).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.
Invitae	RCV000501861	SCV001212165	uncertain significance	Biotinidase deficiency	2021-10-14	criteria provided, single submitter	clinical testing	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. 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"). ClinVar contains an entry for this variant (Variation ID: 143949). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 10400129, 22698809, 24525934, 26589311). This variant is not present in population databases (ExAC no frequency). 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.
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.