Submissions for variant NM_001370658.1(BTD):c.1308A>C (p.Gln436His)

gnomAD frequency: 0.00046  dbSNP: rs80338685

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078065	SCV000230010	pathogenic	not provided	2013-06-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000078065	SCV000238751	pathogenic	not provided	2020-05-20	criteria provided, single submitter	clinical testing	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)
Genetic Services Laboratory, University of Chicago	RCV000001979	SCV000593790	pathogenic	Biotinidase deficiency	2017-03-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001979	SCV000630328	pathogenic	Biotinidase deficiency	2024-01-30	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000001979	SCV000883526	pathogenic	Biotinidase deficiency	2022-05-19	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078065	SCV000888011	pathogenic	not provided	2020-05-30	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000001979	SCV000894300	pathogenic	Biotinidase deficiency	2021-12-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001979	SCV000915029	pathogenic	Biotinidase deficiency	2017-08-30	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000001979	SCV001136348	pathogenic	Biotinidase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000001979	SCV001193856	pathogenic	Biotinidase deficiency	2019-11-12	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000078065	SCV001246041	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BTD: PM3:Very Strong, PM2, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000001979	SCV001367601	pathogenic	Biotinidase deficiency	2018-11-08	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001979	SCV001623320	pathogenic	Biotinidase deficiency	2023-03-16	criteria provided, single submitter	clinical testing	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000001979	SCV001762381	pathogenic	Biotinidase deficiency	2021-06-22	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000001979	SCV002018003	pathogenic	Biotinidase deficiency	2023-05-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV000001979	SCV002499698	pathogenic	Biotinidase deficiency	2022-02-08	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM3,PM7,PP3,PP5,BP1
MGZ Medical Genetics Center	RCV000001979	SCV002579970	likely pathogenic	Biotinidase deficiency	2022-06-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000001979	SCV004040654	pathogenic	Biotinidase deficiency	2024-03-21	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000001979	SCV004175519	pathogenic	Biotinidase deficiency	2022-03-24	criteria provided, single submitter	clinical testing	The p.(Gln456His) variant is a well-established pathogenic variant (PMID: 20301497), reported in multiple individuals and classified as pathogenic by multiple laboratories (ClinVar).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000001979	SCV004183356	pathogenic	Biotinidase deficiency	2022-02-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PM3, PP3
Ambry Genetics	RCV004018539	SCV004915848	pathogenic	Inborn genetic diseases	2021-07-13	criteria provided, single submitter	clinical testing	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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000001979	SCV005052049	pathogenic	Biotinidase deficiency	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000001979	SCV000022137	pathogenic	Biotinidase deficiency	2000-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000001979	SCV000040403	not provided	Biotinidase deficiency		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000001979	SCV000238446	pathogenic	Biotinidase deficiency	2015-05-07	no assertion criteria provided	research	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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251700	SCV001427441	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000001979	SCV001461224	pathogenic	Biotinidase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078065	SCV001930901	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078065	SCV001973629	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751193	SCV005359713	pathogenic	BTD-related disorder	2024-03-22	no assertion criteria provided	clinical testing	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.