ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.683T>C (p.Ile228Thr)

gnomAD frequency: 0.00001  dbSNP: rs397514382
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000021960 SCV000602896 likely pathogenic Biotinidase deficiency 2019-05-23 criteria provided, single submitter clinical testing The BTD c.743T>C; p.Ile248Thr variant (rs397514382) is reported in the literature in at least one individual affected with biotinidase deficiency who carried a second, pathogenic variant in BTD (Cowan 2012). This variant is reported in ClinVar (Variation ID: 25037), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 248 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 likely 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.
Counsyl RCV000021960 SCV000800591 uncertain significance Biotinidase deficiency 2017-11-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284605 SCV001470475 likely pathogenic not provided 2019-10-31 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.
Invitae RCV000021960 SCV001585143 pathogenic Biotinidase deficiency 2023-12-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 248 of the BTD protein (p.Ile248Thr). This variant is present in population databases (rs397514382, gnomAD 0.003%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 22698809, 26810761). ClinVar contains an entry for this variant (Variation ID: 25037). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002228053 SCV002511628 uncertain significance not specified 2022-04-08 criteria provided, single submitter clinical testing Variant summary: BTD c.683T>C (p.Ile228Thr) 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 2e-05 in 251456 control chromosomes. c.683T>C has been reported in the literature as c.743T>C in (p.Ile248Thr) and a compound heterozygous genotype in at-least one individual affected with Biotinidase Deficiency (example, Cowan_2012, Procter_2016). These data do not allow any conclusion about variant significance. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV000021960 SCV004211456 likely pathogenic Biotinidase deficiency 2023-06-05 criteria provided, single submitter clinical testing

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