ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1046C>T (p.Pro349Leu)

gnomAD frequency: 0.00003  dbSNP: rs397514400
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000021982 SCV000800641 uncertain significance Biotinidase deficiency 2017-12-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000021982 SCV002237331 uncertain significance Biotinidase deficiency 2022-09-13 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 369 of the BTD protein (p.Pro369Leu). This variant is present in population databases (rs397514400, gnomAD 0.02%). This missense change has been observed in individual(s) with BTD-related conditions (PMID: 12359137, 29353266). ClinVar contains an entry for this variant (Variation ID: 25059). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000021982 SCV002769158 uncertain significance Biotinidase deficiency 2020-06-11 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a proline to a leucine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (P) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are inconclusive. This variant has been reported as a VUS in ClinVar. It has also been reported in a patient with biotinidase deficiency, who also carried 2 other missense variants in BTD – one in cis and one in trans (PMID:12359137). However, the effect of this variant on the phenotype of that patient is unclear. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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