ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1308A>C (p.Gln436His) (rs80338685)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078065 SCV000230010 pathogenic not provided 2013-06-11 criteria provided, single submitter clinical testing
GeneDx RCV000078065 SCV000238751 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing 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 et al., 1997).
Genetic Services Laboratory, University of Chicago RCV000001979 SCV000593790 pathogenic Biotinidase deficiency 2017-03-24 criteria provided, single submitter clinical testing
Invitae RCV000001979 SCV000630328 pathogenic Biotinidase deficiency 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 456 of the BTD protein (p.Gln456His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs80338685, ExAC 0.07%). This variant is a well known BTD deficiency allele (PMID: 9232193). It has been reported as homozygous and in combination with other BTD variants in newborn screening positive and in symptomatic individuals (PMID: 11313766, 10400129, 10801053, 25423671, 26810761, 27329734, 24797656). ClinVar contains an entry for this variant (Variation ID: 1902). This variant has been associated with profound and partial deficiency of BTD enzyme activity (PMID: 11313766, 9232193, 9654207, 23644139, 27329734, 24797656). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000001979 SCV000883526 pathogenic Biotinidase deficiency 2019-10-01 criteria provided, single submitter clinical testing The BTD c.1368A>C; p.Gln456His variant (rs80338685) 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 Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Fulgent Genetics,Fulgent Genetics RCV000001979 SCV000894300 pathogenic Biotinidase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000078065 SCV001246041 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
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 2021-04-23 criteria provided, single submitter clinical testing Variant summary: BTD c.1308A>C (p.Gln436His, also known as c.1368A>C/p.Gln456His in NM_000060) 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 expected 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). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=15, likely benign n=1). 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.
OMIM RCV000001979 SCV000022137 pathogenic Biotinidase deficiency 2000-03-01 no assertion criteria provided literature only
GeneReviews RCV000001979 SCV000040403 pathologic Biotinidase deficiency 2011-03-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Research and Development, ARUP Laboratories RCV000001979 SCV000042681 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria 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

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