rs369102875
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_001370658.1(BTD):c.565C>T(p.Arg189Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189H) has been classified as Pathogenic.
Frequency
Consequence
NM_001370658.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.565C>T | p.Arg189Cys | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.565C>T | p.Arg189Cys | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251480Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135912
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727248
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74288
ClinVar
Submissions by phenotype
Biotinidase deficiency Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 05, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2023 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BTD: PM2, PM3, PM5 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2021 | 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at