Submissions for variant NM_001370658.1(BTD):c.399G>A (p.Glu133=)

dbSNP: rs397514360

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000425369	SCV000511171	likely pathogenic	not provided	2016-09-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021928	SCV000630333	pathogenic	Biotinidase deficiency	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change affects codon 153 of the BTD mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BTD protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs397514360, gnomAD 0.0009%). This variant has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, 10400129; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 25009). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000425369	SCV001758861	likely pathogenic	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear; This variant is associated with the following publications: (PMID: 11865279, 11668630, 20556795, 10400129, 9396567)
Baylor Genetics	RCV000021928	SCV004211442	likely pathogenic	Biotinidase deficiency	2023-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000021928	SCV004223036	likely pathogenic	Biotinidase deficiency	2023-11-21	criteria provided, single submitter	clinical testing	Variant summary: BTD c.399G>A (p.Glu133Glu) alters the conserved, last nucleotide of exon 3 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions have yet to be confirmed by functional studies, although one study attempted to confirm a splicing impact but was unable to detect any aberrantly spliced transcripts or transcripts with the variant of interest in patients (e.g., Pomponio_1997). These findings suggest mRNA produced from the variant allele may be rapidly degraded. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.399G>A has been reported in the literature in several compound heterozygous individuals affected with Biotinidase Deficiency (e.g., Pomponio_1997, Norrgard_1999, Wolf_2002). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that biotinyl-hydrolase activity was <10% of normal activity in serum from patients harboring a null variant in trans (e.g., Pomponio_1997, Norrgard_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10400129, 9396567, 11865279). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.