Submissions for variant NM_001370658.1(BTD):c.835G>C (p.Ala279Pro)

dbSNP: rs1157567876

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508475	SCV000600948	likely pathogenic	not provided	2016-11-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000715008	SCV001516323	pathogenic	Biotinidase deficiency	2024-02-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 299 of the BTD protein (p.Ala299Pro). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 439039). 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%. This variant disrupts the p.Ala299 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 10394193), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000715008	SCV004211491	likely pathogenic	Biotinidase deficiency	2023-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689768	SCV005184371	uncertain significance	not specified	2024-05-01	criteria provided, single submitter	clinical testing	Variant summary: BTD c.835G>C (p.Ala279Pro) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase domain (IPR003010) of 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 8e-06 in 251396 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.835G>C has been reported in the literature in individuals affected with Biotinidase Deficiency (examples: Wiltink_2016, Procter_2016 ). These data do not allow any conclusion about variant significance. 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: 36684547). ClinVar contains an entry for this variant (Variation ID: 439039). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000715008	SCV005660286	likely pathogenic	Biotinidase deficiency	2024-05-06	criteria provided, single submitter	clinical testing