Submissions for variant NM_001370658.1(BTD):c.1372G>C (p.Ala458Pro)

dbSNP: rs181396238

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484254	SCV000566960	likely pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19757147)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022014	SCV001231274	pathogenic	Biotinidase deficiency	2024-02-02	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 478 of the BTD protein (p.Ala478Pro). This variant is present in population databases (rs181396238, gnomAD 0.01%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 19757147). ClinVar contains an entry for this variant (Variation ID: 25089). 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.Ala478 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 26810761), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000022014	SCV003835677	likely pathogenic	Biotinidase deficiency	2024-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022014	SCV005203762	pathogenic	Biotinidase deficiency	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: BTD c.1372G>C (p.Ala458Pro) results in a non-conservative amino acid change in 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 1.6e-05 in 251444 control chromosomes. c.1372G>C has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with Biotinidase Deficiency (example, Sarafoglou_2009, Sharma_2024). 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. The most pronounced variant effect results in <10% of normal activity in an individual with a homozygous genotype (Sarafoglou_2009). The following publications have been ascertained in the context of this evaluation (PMID: 36684547, 20556795, 19757147, 38299772). ClinVar contains an entry for this variant (Variation ID: 25089). Based on the evidence outlined above, the variant was classified as pathogenic.