chr3-15645224-A-C
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001370658.1(BTD):c.1308A>C(p.Gln436His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00070 ( 0 hom. )
Consequence
BTD
NM_001370658.1 missense
NM_001370658.1 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 1.13
Genes affected
BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-15645224-A-C is Pathogenic according to our data. Variant chr3-15645224-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645224-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.1308A>C | p.Gln436His | missense_variant | 4/4 | ENST00000643237.3 | NP_001357587.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.1308A>C | p.Gln436His | missense_variant | 4/4 | NM_001370658.1 | ENSP00000495254 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000447 AC: 68AN: 152124Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000414 AC: 104AN: 251420Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135878
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GnomAD4 exome AF: 0.000699 AC: 1022AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.000664 AC XY: 483AN XY: 727246
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GnomAD4 genome AF: 0.000447 AC: 68AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74432
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:28Benign:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Biotinidase deficiency Pathogenic:20Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 30, 2017 | The BTD c.1368A>C (p.Gln456His) missense variant is described as one of the most common variants in individuals with biotinidase deficiency (Norrgard et al. 1997). The p.Gln456His variant has been reported in at least 16 individuals with partial or profound biotinidase deficiency including two in a homozygous state and 14 in a compound heterozygous state (Norrgard et al. 1997; Thodi et al. 2013; Wolf 2017; Borsatto et al. 2017). The p.Gln456His variant was absent from 632 controls (Norrgard et al. 1997) but is reported at a frequency of 0.00151 in the European American population of the Exome Sequencing Project. Serum from a homozygous individual showed reduced cross reacting material to a polyclonal antibody compared with serum from normal controls, and decreased or no activity of biotinyl-hydrolase and biotinyl-transferase was also observed (Norrgard et al. 1997). Based on the evidence, the p.Gln456His variant is classified as pathogenic for biotinidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000060.2(BTD):c.1368A>C(Q456H) is classified as pathogenic in the context of biotinidase deficiency. Sources cited for classification include the following: PMID 9232193, 11313766, 22698809, 17185019, 20224900, 23644139 and 26361991. Classification of NM_000060.2(BTD):c.1368A>C(Q456H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 14, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 19, 2022 | The BTD c.1308A>C; p.Gln436His variant (rs80338685, c.1368A>C; p.Gln456His on NM_000060.3) is reported to be the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States (Norrgard 1997). This variant is reported in ClinVar (Variation ID: 1902). It is found in the general population with an overall allele frequency of 0.04% (115/282806 alleles) in the Genome Aggregation Database. The glutamine at codon 456 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, the variant enzyme in the homozygous state has very low biotinyl-hydrolase activity and lacks biotinyl-transferase activity (Norrgard 1997). Based on available information, this variant is considered to be severely pathogenic. References: Norrgard KJ et al. Mutation (Q456H) is the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Biochem Mol Med. 1997 Jun;61(1):22-7. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jun 22, 2021 | This BTD variant (rs80338685) is rare (<0.1%) in a large population dataset (gnomAD: 115/282806 total alleles, 0.04%, no homozygotes) and has an entry in ClinVar. It is a common cause of profound bioitinidase deficiency (less than 10% mean normal activity in serum) when it occurs in a homozygous or compound heterozygous state with another pathogenic BTD variant and is the most common BTD variant identified in children with profound biotinidase deficiency by newborn screening in the United States. This variant has been reported in a compound heterozygous state (in trans) with the complex allele c.[451G>A;1207G>C] in multiple unrelated individuals with profound biotinidase deficiency. We consider c.1308A>C to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 456 of the BTD protein (p.Gln456His). This variant is present in population databases (rs80338685, gnomAD 0.08%). This missense change has been observed in individual(s) with BTD-related conditions (PMID: 10400129, 10801053, 11313766, 24797656, 25423671, 26810761, 27329734). ClinVar contains an entry for this variant (Variation ID: 1902). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 08, 2018 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 16, 2023 | Variant summary: BTD c.1308A>C (p.Gln436His) 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 0.00041 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00041 vs 0.0046), allowing no conclusion about variant significance. c.1308A>C has been reported in the literature in multiple individuals affected with Biotinidase Deficiency (e.g. Norrgard_1997, Wolf_2017). These data indicate that the variant is very likely to be associated with disease. Multiple publications report that biotinase activity in patients carrying this variant or in mutant plasmid has <20% of normal activity (e.g. Norrgard_1997, Wolf_2017, Liu_2018). 19 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with 18 submitters classifying the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 03, 2022 | ACMG classification criteria: PM2, PM3, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 24, 2022 | The p.(Gln456His) variant is a well-established pathogenic variant (PMID: 20301497), reported in multiple individuals and classified as pathogenic by multiple laboratories (ClinVar). - |
Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | May 07, 2015 | This patient is a carrier of a heterozygous pathogenic variant in the BTD gene associated with autosomal recessive biotinidase deficiency (MIM 253260). This BTD variant (c.1374A>C) was identified in several patients in both the homozygous and compound heterozygous state, and is one of the most common pathogenic mutations identified in this gene through newborn screening programs in populations of northern European ancestry (Norrgard et al. 1997, PMID 9232193; Wolf et al. 1997, PMID: 9375914; Norrgard et al. 1999, PMID: 10400129; Pomponio et al. 2000, PMID: 10801053). Biochemical analyses of patients with this mutation have supported the role this mutation plays in causing biotinidase deficiency. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Feb 08, 2022 | ACMG categories: PS3,PM3,PM7,PP3,PP5,BP1 - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 15, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2020 | Functional analysis found Q456H is associated with significantly reduced enzyme activity compared to wild-type (Liu et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26810761, 27329734, 11313766, 9375914, 22975760, 25087612, 9232193, 27657684, 28971021, 9654207, 23644139, 24797656, 10400129, 10801053, 25423671, 29359854, 31980526) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 11, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 30, 2020 | This variant is the most common pathogenic variant associated with profound biotinidase deficiency (PMID: 9232193 (1997)). Individuals who are compound heterozygous for this variant and other pathogenic BTD variants, or homozygous for this variant, have been reported to be affected with partial or profound biotinidase deficiency in the published literature (PMIDs: 9232193 (1997), 9654207 (1998), 10801053 (2000), 11668630 (2001), 17185019 (2007), 22698809 (2012), 23644139 (2013), 26361991 (2015), 27329734 (2016), 27657684 (2017), and 28971021 (2017)). In addition, a functional analysis on the effect of this variant reports decreased biotinidase activity in vitro (PMID: 29359854 (2018)). Therefore, the variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | BTD: PM3:Very Strong, PM2, PS3:Supporting - |
BTD-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 22, 2024 | The BTD c.1368A>C variant is predicted to result in the amino acid substitution p.Gln456His. This sequence variant is one of the most commonly reported variants causative for profound biotinidase deficiency (Norrgard et al. 1997. PubMed ID: 9232193; Karaca et al. 2015. PubMed ID: 25754625; Porta et al. 2017. PubMed ID: 28971021). This variant is reported in 0.077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2021 | The c.1368A>C (p.Q456H) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a A to C substitution at nucleotide position 1368, causing the glutamine (Q) at amino acid position 456 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the BTD c.1368A>C alteration was observed in 0.04% (115/282806) of total alleles studied, with a frequency of 0.08% (100/129138) in the European (non-Finnish) subpopulation. This mutation has been identified in the homozygous and compound heterozygous states in multiple unrelated patients with biotinidase deficiency (Norrgard, 1999; Pomponio, 2000; Funghini, 2020). The Q456H mutation is the most common BTD mutation ascertained by newborn screening in the United States, having been identified on 28% of alleles of children with profound biotinidase deficiency (Norrgard, 1997). Serum from a patient who was homozygous for the Q456H mutation had greatly reduced quantities of cross-reacting material to anti-biotinidase antibody, profoundly deficient biotinyl-hydrolase activity, and no biotinyl-transferase activity (Norrgard, 1997). The p.Q456H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Intellectual disability Benign:1
Likely benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;D;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;M;.;.;.;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.;.;.;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.;.;D;D
Sift4G
Uncertain
.;D;.;.;.;D;D
Polyphen
1.0
.;.;D;.;.;.;.
Vest4
0.97, 0.98, 0.96
MutPred
0.94
.;.;Gain of sheet (P = 0.0477);.;.;.;.;
MVP
0.96
MPC
0.41
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at