Submissions for variant NM_001370658.1(BTD):c.565C>T (p.Arg189Cys)

gnomAD frequency: 0.00005  dbSNP: rs369102875

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537387	SCV000630339	pathogenic	Biotinidase deficiency	2024-02-07	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 209 of the BTD protein (p.Arg209Cys). This variant is present in population databases (rs369102875, gnomAD 0.008%). This missense change has been observed in individuals with biotinidase deficiency (PMID: 26810761, 33189081; Invitae). ClinVar contains an entry for this variant (Variation ID: 458809). 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.Arg209 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24797656, 25754625, 26361991). 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.
Counsyl	RCV000537387	SCV000788646	uncertain significance	Biotinidase deficiency	2017-10-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000537387	SCV001652750	uncertain significance	Biotinidase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001591206	SCV001814815	likely pathogenic	not provided	2023-08-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 27760515, 29353266, 34426522, 34271776, 33189081, 26810761)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778993	SCV002015196	uncertain significance	not specified	2021-10-06	criteria provided, single submitter	clinical testing	Variant summary: BTD c.565C>T (p.Arg189Cys), also known as c.625C>T (p.R209C), 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 5.6e-05 in 251480 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.565C>T has been reported in the literature in individuals affected with Biotinidase Deficiency as well as in two asymptomatic infants (Procter_2016, Tanyalcin_2016, Seker Yilmaz_2018, Ercan_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV002527692	SCV003697307	uncertain significance	Inborn genetic diseases	2022-09-19	criteria provided, single submitter	clinical testing	The c.625C>T (p.R209C) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a C to T substitution at nucleotide position 625, causing the arginine (R) at amino acid position 209 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000537387	SCV004211398	likely pathogenic	Biotinidase deficiency	2024-03-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001591206	SCV005092881	likely pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BTD: PM2, PM3, PM5
Fulgent Genetics, Fulgent Genetics	RCV000537387	SCV005660274	likely pathogenic	Biotinidase deficiency	2024-01-05	criteria provided, single submitter	clinical testing