ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000078065 SCV000883526 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing The BTD c.1368A>C; p.Gln456His variant (rs80338685) is reported multiple times in the ClinVar database as pathogenic (Variation ID: 1902), and reported to be the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States (Norrgard 1997). The variant enzyme in the homozygous state has very low biotinyl-hydrolase activity and lacks biotinyl-transferase activity (Norrgard 1997). Therefore, this variant is considered severely pathogenic. REFERENCES Link to ClinVar database for p.Gln456His: 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.
Counsyl RCV000001979 SCV000486493 pathogenic Biotinidase deficiency 2016-06-15 criteria provided, single submitter clinical testing
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078065 SCV000230010 pathogenic not provided 2013-06-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000001979 SCV000894300 pathogenic Biotinidase deficiency 2018-10-31 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).
GeneReviews RCV000001979 SCV000040403 pathologic Biotinidase deficiency 2011-03-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000001979 SCV000593790 pathogenic Biotinidase deficiency 2017-03-24 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.
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.
OMIM RCV000001979 SCV000022137 pathogenic Biotinidase deficiency 2000-03-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078065 SCV000888011 pathogenic not provided 2015-11-17 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000001979 SCV000042681 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only

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