ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1552C>T (p.Arg518Cys)

gnomAD frequency: 0.00011  dbSNP: rs80338686
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790794 SCV000230006 pathogenic not provided 2013-10-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000001975 SCV000711423 pathogenic Biotinidase deficiency 2016-09-02 criteria provided, single submitter clinical testing The p.Arg538Cys variant in BTD has been previously identified in at least 5 comp ound heterozygous and 2 homozygous individuals with severe biotinidase deficienc y and it is the second most common mutation in the biotinidase gene that causes profound biotinidase deficiency in symptomatic children. All these patients had no biotinyl transferase activity in their serum and <10% of mean normal biotiny l-hydrolase activity (Pomponio 1997). This variant has also been identified in 8 /114,620 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs80338686); however, this frequency is low enough to b e consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for biotinidase deficiency in an autoso mal recessive manner based upon case and allelic observations and functional evi dence.
Invitae RCV000001975 SCV000754947 pathogenic Biotinidase deficiency 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 538 of the BTD protein (p.Arg538Cys). This variant is present in population databases (rs80338686, gnomAD 0.01%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9099842, 27207447, 27657684). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1898). 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%. This variant disrupts the p.Arg538 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22698809; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000001975 SCV000894302 pathogenic Biotinidase deficiency 2022-02-09 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000001975 SCV001194032 pathogenic Biotinidase deficiency 2019-12-19 criteria provided, single submitter clinical testing NM_000060.2(BTD):c.1612C>T(R538C) is classified as pathogenic in the context of biotinidase deficiency. Sources cited for classification include the following: PMID 9099842 and 17185019. Classification of NM_000060.2(BTD):c.1612C>T(R538C) 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000790794 SCV001470474 pathogenic not provided 2020-08-10 criteria provided, single submitter clinical testing The c.1612C>T (p.Arg538Cys) variant (also known as R538C) is a common cause of profound biotinidase deficiency reported in the published literature (PMID: 29728376 (2018), 27657684 (2017), 27207447 (2017), 26810761 (2016), 26361991 (2015), 9158148 (1997), and 9099842 (1997)). Variant is found in at a symptomatic patient. It is predicted to have a damaging effect on the protein. It occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and have a phenotype known to be consistent with disease. It is also damaging to protein function relevant to disease mechanism.
CeGaT Center for Human Genetics Tuebingen RCV000790794 SCV001962471 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing BTD: PM3:Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Moderate, PP1
Revvity Omics, Revvity Omics RCV000001975 SCV002022092 pathogenic Biotinidase deficiency 2023-05-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000001975 SCV002048493 pathogenic Biotinidase deficiency 2021-07-23 criteria provided, single submitter clinical testing The BTD c.1612C>T; p.Arg538Cys variant (rs80338686) is the second most common pathogenic variant in the BTD gene and has been reported in both the homozygous and compound heterozygous states in multiple individuals with profound BTD deficiency (Murry 2018, Pomponio 1997). This variant is reported in ClinVar (Variation ID: 1898). It is found in the general population with an overall allele frequency of 0.007% (20/272304 alleles) in the Genome Aggregation Database. The arginine at codon 538 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be severely pathogenic. REFERENCES Murry JB et al. Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report. Cold Spring Harb Mol Case Stud. 2018 Aug 1;4(4). Pomponio RJ et al. Arg538 to Cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of profound biotinidase deficiency in symptomatic children. Hum Genet. 1997 Apr;99(4):506-12.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001975 SCV002556006 pathogenic Biotinidase deficiency 2022-06-20 criteria provided, single submitter clinical testing Variant summary: BTD c.1552C>T (p.Arg518Cys) 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 7.5e-05 in 240906 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (7.5e-05 vs 0.0046), allowing no conclusion about variant significance. c.1552C>T has been reported in the literature in multiple individuals affected with Biotinidase Deficiency. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV003242960 SCV003937131 pathogenic Inborn genetic diseases 2023-05-30 criteria provided, single submitter clinical testing The c.1612C>T (p.R538C) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a C to T substitution at nucleotide position 1612, causing the arginine (R) at amino acid position 538 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.007% (20/272304) total alleles studied. The highest observed frequency was 0.014% (1/7044) of Other alleles. This alteration has been identified in the homozygous and compound heterozygous state in multiple unrelated patients with biotinidase deficiency (Pomponio, 1997; Mil&aacute;nkovics, 2007; Borsatto, 2014; Girard, 2017; Murry, 2018; Wolf, 2019; Maguolo, 2021; Forny, 2022). Additionally, other alterations at the same codon, c.1612C>A (p.R538S) and c.1613G>A (p.R538H), have been reported previously in the homozygous and compound heterozygous state in individuals with biotinidase deficiency (Sarafoglou, 2009; Cowan, 2012; Procter, 2016; Liu, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Preventiongenetics, part of Exact Sciences RCV003421895 SCV004116633 pathogenic BTD-related condition 2023-10-02 criteria provided, single submitter clinical testing The BTD c.1612C>T variant is predicted to result in the amino acid substitution p.Arg538Cys. This variant has been reported in the homozygous state or with a second BTD variant in individuals with biotinidase deficiency (Pomponio et al. 1997. PubMed ID: 9099842; Milánkovics et al. 2007. PubMed ID: 17185019; Cowan et al. 2012. PubMed ID: 22698809; Wolf 2017. PubMed ID: 27657684). It has been reported to be one of the most common variants associated with profound biotinidase deficiency (Pomponio et al. 1997. PubMed ID: 9099842; Wolf 2012. PubMed ID: 22241090). Alternate substitutions impacting the same amino acid (p.Arg538His, p.Arg538Leu) have been reported in individuals with biotinidase deficiency, although both were reported as likely partial deficiency variants (Liu et al. 2018. PubMed ID: 29359854; Manguolo et al. 2021. PubMed ID: 34136440). The c.1612C>T (p.Arg538Cys) variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-15686975-C-T). Taken together, this variant is interpreted as pathogenic.
Baylor Genetics RCV000001975 SCV004211391 pathogenic Biotinidase deficiency 2023-10-30 criteria provided, single submitter clinical testing
OMIM RCV000001975 SCV000022133 pathogenic Biotinidase deficiency 1997-04-01 no assertion criteria provided literature only
GeneReviews RCV000001975 SCV000040404 not provided Biotinidase deficiency no assertion provided literature only
Natera, Inc. RCV000001975 SCV001461230 pathogenic Biotinidase deficiency 2020-09-16 no assertion criteria provided clinical testing
Genetic Services Laboratory, University of Chicago RCV000790794 SCV003839294 pathogenic not provided 2022-06-21 no assertion criteria provided clinical testing DNA sequence analysis of the BTD gene demonstrated a sequence change, c.1552C>T, in exon 4 that results in an amino acid change, p.Arg518Cys. This sequence change has previously been reported in the homozygous or compound heterozygous state in multiple individuals with biotinidase deficiency and has been found to co-segregate with disease in families (PMID: 9099842, 27207447). Homozygous individuals have been found to have no enzyme activity. This sequence change has been described in the gnomAD database with a frequency of 0.007% in the overall population (dbSNP rs80338686). The p.Arg518Cys change affects a highly conserved amino acid residue located in a domain of the BTD protein that is not known to be functional. The p.Arg518Cys amino acid change occurs in a region of the BTD gene where other missense sequence changes have been described in individuals with BTD-related disorders.

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