ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.908A>G (p.His303Arg) (rs397507176)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723564 SCV000109921 uncertain significance not provided 2012-12-10 criteria provided, single submitter clinical testing
GeneDx RCV000723564 SCV000516150 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing The H323R variant in the BTD gene has been reported previously in the compound heterozygous state in a child with partial biotinidase deficiency at 22.5% of normal enzyme activity (Swango et al., 1998). The H323R variant is observed in 517/30782 (1.68%) alleles from individuals of South Asian background, including 8 unrelated homozygous individuals in large population cohorts (Lek et al., 2016). The H323R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret H323R as a variant of uncertain significance.
Invitae RCV000021978 SCV000630341 uncertain significance Biotinidase deficiency 2018-02-15 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 323 of the BTD protein (p.His323Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs397507176, ExAC 1.6%). This variant has been reported in the literature in two individuals affected with partial BTD deficiency who showed 10-30% of normal BTD enzymatic activity (PMID: 9654207, 26361991), in combination with a BTD pathogenic variant in an individual with normal enzymatic activity (PMID: 26361991), and in one individual newborn screening positive for BTD deficiency but with normal enzymatic activity after confirmatory analyses (PMID: 27329734). ClinVar contains an entry for this variant (Variation ID: 38278). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that has been reported in individuals with partial BTD deficiency as well as in individuals with normal enzymatic activity. Further genetic and/or functional data are needed to classify this variant conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000622271 SCV000742653 likely pathogenic Inborn genetic diseases 2017-07-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000723564 SCV001134045 uncertain significance not provided 2019-01-27 criteria provided, single submitter clinical testing
Mendelics RCV000021978 SCV001136346 uncertain significance Biotinidase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000021978 SCV001522810 pathogenic Biotinidase deficiency 2019-06-24 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Research and Development, ARUP Laboratories RCV000021978 SCV000042648 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only
Natera, Inc. RCV000021978 SCV001454451 uncertain significance Biotinidase deficiency 2017-09-25 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.