Submissions for variant NM_001370658.1(BTD):c.185C>T (p.Ala62Val)

dbSNP: rs397507171

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000021907	SCV000800679	uncertain significance	Biotinidase deficiency	2018-03-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001171830	SCV001334700	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800312	SCV002047133	uncertain significance	not specified	2021-05-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021907	SCV003525315	pathogenic	Biotinidase deficiency	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 82 of the BTD protein (p.Ala82Val). This variant is present in population databases (rs397507171, gnomAD 0.003%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 24989). 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.Ala82 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 29995633), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001800312	SCV005040295	uncertain significance	not specified	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: BTD c.185C>T (p.Ala62Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of four 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 251408 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.185C>T has been reported in the literature at a compound heterozygous state along with a pathogenic missense in at-least one individual affected with Biotinidase Deficiency (example, 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. Additionally, at least two variants at the Ala62 residue have been reported as DM in HGMD (p.A62D and p.A62G), suggesting that this codon might be functionally important. However, further evidence is needed to validate the pathogenicity of those two variants. The following publication have been ascertained in the context of this evaluation (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 24989). Based on the evidence outlined above, the variant was classified as uncertain significance.