ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.875G>A (p.Gly292Asp)

gnomAD frequency: 0.00001  dbSNP: rs377651057
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000021977 SCV000800608 uncertain significance Biotinidase deficiency 2017-10-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000021977 SCV001588463 pathogenic Biotinidase deficiency 2020-12-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly312 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 12359137), which suggests that this may be a clinically significant amino acid residue. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25055). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 312 of the BTD protein (p.Gly312Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004700265 SCV005203356 uncertain significance not specified 2024-07-05 criteria provided, single submitter clinical testing Variant summary: BTD c.875G>A (p.Gly292Asp) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase domain profile (Carbon-nitrogen hydrolase domain profile) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251388 control chromosomes. c.875G>A has been reported in the literature as homozygous genotype in an individual affected with Biotinidase Deficiency (Pomponio_1997). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9396567). ClinVar contains an entry for this variant (Variation ID: 25055). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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