Submissions for variant NM_001370658.1(BTD):c.383G>A (p.Arg128His)

gnomAD frequency: 0.00005  dbSNP: rs367902696

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490188	SCV000576611	uncertain significance	not provided	2024-04-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 20556795, 33312878, 20224900)
Fulgent Genetics, Fulgent Genetics	RCV000021924	SCV000894297	likely pathogenic	Biotinidase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021924	SCV003280764	likely pathogenic	Biotinidase deficiency	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 148 of the BTD protein (p.Arg148His). This variant is present in population databases (rs367902696, gnomAD 0.01%). This missense change has been observed in individuals with biotinidase deficiency (PMID: 20224900, 33312878). ClinVar contains an entry for this variant (Variation ID: 25005). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002513163	SCV003549823	likely pathogenic	Inborn genetic diseases	2021-08-27	criteria provided, single submitter	clinical testing	The c.443G>A (p.R148H) alteration is located in exon 3 (coding exon 3) of the BTD gene. This alteration results from a G to A substitution at nucleotide position 443, causing the arginine (R) at amino acid position 148 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (16/282674) total alleles studied. The highest observed frequency was 0.03% (2/7222) of Other alleles. This alteration has been identified in the compound heterozygous state, confirmed in trans by parental testing, with second BTD variant in Italian neonate with partial biotinidase deficiency (Funghini, 2020). It has also been reported along with a second BTD variant in an individual with reduced biotinidase activity in plasma (Ohlsson, 2010). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226165	SCV003922837	uncertain significance	not specified	2024-12-03	criteria provided, single submitter	clinical testing	Variant summary: BTD c.383G>A (p.Arg128His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251272 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BTD causing Biotinidase Deficiency (6e-05 vs 0.0046), allowing no conclusion about variant significance. c.383G>A has been reported in the literature in the compound heterozygous state in an individual affected with partial biotinidase deficiency and in the mother of a proband with partial biotinidase deficiency, who was asymptomatic but was found to have decreased plasma biotinidase activity outside the normal range (Ohlsson_2010, Funghini_2020). At least one publication reports a presumed activity decrease (50%-90% of normal activity) in a patient sample who carried a low-activity frameshift on the other allele (example, Funghini_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33312878, 20224900). ClinVar contains an entry for this variant (Variation ID: 25005). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000021924	SCV004211403	likely pathogenic	Biotinidase deficiency	2024-03-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000021924	SCV001132347	uncertain significance	Biotinidase deficiency	2019-05-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000021924	SCV002081550	likely pathogenic	Biotinidase deficiency	2021-04-26	no assertion criteria provided	clinical testing