rs80338685
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
Consequence
NM_001370658.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BTD | NM_001370658.1 | c.1308A>C | p.Gln436His | missense_variant | Exon 4 of 4 | ENST00000643237.3 | NP_001357587.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000447 AC: 68AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000414 AC: 104AN: 251420Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135878
GnomAD4 exome AF: 0.000699 AC: 1022AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.000664 AC XY: 483AN XY: 727246
GnomAD4 genome 0.000447 AC: 68AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74432
ClinVar
Submissions by phenotype
Biotinidase deficiency Pathogenic:20Other:1
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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. -
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ACMG classification criteria: PM2, PM3, PP3 -
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. -
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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. -
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). 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%. For these reasons, this variant has been classified as Pathogenic. -
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3. -
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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. -
ACMG categories: PS3,PM3,PM7,PP3,PP5,BP1 -
The p.(Gln456His) variant is a well-established pathogenic variant (PMID: 20301497), reported in multiple individuals and classified as pathogenic by multiple laboratories (ClinVar). -
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. -
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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. -
not provided Pathogenic:6
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BTD: PM3:Very Strong, PM2, PS3:Supporting -
The BTD c.1368A>C (p.Gln456His) variant has been reported in the published literature as 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), 28971021 (2017), and 33312878 (2020)). In addition, a functional analysis on the effect of this variant reports decreased biotinidase activity in vitro (PMID: 29359854 (2018)). The frequency of this variant in the general population, 0.001 (12/11606 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 pathogenic. -
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) -
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BTD-related disorder Pathogenic:1
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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at