Submissions for variant NM_001370658.1(BTD):c.1406A>C (p.Asn469Thr)

gnomAD frequency: 0.00002  dbSNP: rs104893692

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000001980	SCV000441834	uncertain significance	Biotinidase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The BTD c.1466A>C (Asn489Thr) variant has been reported in three studies and was found in a homozygous state in one individual with 10.8% of the mean normal biotinyl hydrolase activity (Pomponio et al. 1998). This individual was also homozygous for an additional polymorphism, and each of the individual's parents was shown to be a heterozygous carrier of both variants. Control data are unavailable for this variant, which is reported at a frequency of 0.00046 in the East Asian population of the Exome Aggregation Consortium. The p.Asn489Thr variant is present in a well-conserved residue and is predicted to abolish a putative N-linked glycosylation site (Pomponio et al. 1998; Pindolia et al. 2010). Based on the evidence, the p.Asn489Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for biotinidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000001980	SCV000800649	uncertain significance	Biotinidase deficiency	2018-01-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001980	SCV002288117	likely pathogenic	Biotinidase deficiency	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 489 of the BTD protein (p.Asn489Thr). This variant is present in population databases (rs104893692, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9705240; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1903). 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 80%. This variant disrupts the p.Asn489 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 28498829), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV002272006	SCV002558646	uncertain significance	not provided	2022-01-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9705240, 20556795)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230341	SCV003929213	uncertain significance	not specified	2023-04-28	criteria provided, single submitter	clinical testing	Variant summary: BTD c.1406A>C (p.Asn469Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three 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.1406A>C has been reported in the literature as a homozygous genotype in at-least one individual affected with Biotinidase Deficiency (example, Pomponio_1998). 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: 28498829, 20556795, 9705240). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=3; LP, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV000001980	SCV000022138	pathogenic	Biotinidase deficiency	1998-06-01	no assertion criteria provided	literature only