ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1535C>T (p.Thr512Met) (rs104893688)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001974 SCV000220463 pathogenic Biotinidase deficiency 2014-06-29 criteria provided, single submitter literature only
GeneDx RCV000185809 SCV000238753 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The T532M missense variant in the BTD gene has been reported previously in association with profound biotinidase deficiency (Pomponio et al., 2000).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185809 SCV000330913 pathogenic not provided 2015-08-21 criteria provided, single submitter clinical testing
Invitae RCV000001974 SCV000630330 pathogenic Biotinidase deficiency 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 532 of the BTD protein (p.Thr532Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs104893688, ExAC 0.009%). This variant has been reported to be a common cause of biotinidase deficiency in Mediterranean populations, although it has also been described in affected individuals from other ethnic backgrounds (PMID: 9654207, 10801053, 21752405, 22698809, 10400129, 22011816, 27657684). ClinVar contains an entry for this variant (Variation ID: 1897). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Although these predictions have not been confirmed by direct functional studies, homozygous individuals show 10-40% of serum biotinidase activity (PMID: 10400129, 10801053, 25174816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000185809 SCV000888012 pathogenic not provided 2020-08-10 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.
Fulgent Genetics,Fulgent Genetics RCV000001974 SCV000894301 pathogenic Biotinidase deficiency 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000001974 SCV001156597 pathogenic Biotinidase deficiency 2018-10-18 criteria provided, single submitter clinical testing The BTD c.1595C>T; p.Thr532Met variant (rs104893688), is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with partial to profound biotinidase deficiency (Cowan 2012, Funghini 2002, Laszlo 2003, Norrgard 1999, Ohlsson 2010, Pomponio 2000, Swango 1998, Wiltink 2016, Wolf 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 1897), and is found in the non-Finnish European population with an allele frequency of 0.015% (19/125,971 alleles) in the Genome Aggregation Database. The threonine at codon 532 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Thr532Met variant is considered to be severely pathogenic. References: Cowan TM et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug;106(4):485-7. Funghini S et al. Two new mutations in children affected by partial biotinidase deficiency ascertained by newborn screening. J Inherit Metab Dis. 2002 Aug;25(4):328-30. Laszlo A et al. Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. J Inherit Metab Dis. 2003;26(7):693-8. Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. Ohlsson A et al. Profound biotinidase deficiency: a rare disease among native Swedes. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S175-8. Pomponio RJ et al. Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis. 2000 Mar;23(2):120-8. Swango KL et al. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet. 1998 May;102(5):571-5. Wiltink RC et al. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations. Eur J Hum Genet. 2016 Oct;24(10):1424-9. Wolf B. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000001974 SCV001369636 pathogenic Biotinidase deficiency 2020-03-13 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PM3,PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001974 SCV001478654 pathogenic Biotinidase deficiency 2021-04-20 criteria provided, single submitter clinical testing Variant summary: BTD c.1535C>T (p.Thr512Met, also known as c.1595C>T/p.Thr532Met in NM_000060) results in a non-conservative amino acid change located in the Vanin, C-terminal domain (IPR043957) of 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 6.9e-05 in 245398 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (6.9e-05 vs 0.0046), allowing no conclusion about variant significance. This variant has been reported in the literature in multiple individuals (both homozygous and compound heterozygous state) affected with partial to profound Biotinidase Deficiency (example: Pomponio_2000, Lara_2015). These data indicate that the variant is very likely to be associated with disease. Less than 10% of mean normal enzymatic activity was seen in serum or plasma of patients who were homozygous for the variant of interest (Pomponio_2000). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001974 SCV000022132 pathogenic Biotinidase deficiency 2000-03-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000001974 SCV000042696 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only
Natera, Inc. RCV000001974 SCV001461229 pathogenic Biotinidase deficiency 2020-09-16 no assertion criteria provided clinical testing

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