Submissions for variant NM_001370658.1(BTD):c.419G>T (p.Cys140Phe)

dbSNP: rs745343884

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693060	SCV000820914	pathogenic	Biotinidase deficiency	2021-06-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys160 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 25174816), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of biotinidase deficiency (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 571821). This variant is present in population databases (rs745343884, ExAC 0.006%). This sequence change replaces cysteine with phenylalanine at codon 160 of the BTD protein (p.Cys160Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689858	SCV005184714	uncertain significance	not specified	2024-05-14	criteria provided, single submitter	clinical testing	Variant summary: BTD c.419G>T (p.Cys140Phe) 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 4e-06 in 251084 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.419G>T in individuals affected with Biotinidase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 571821). Based on the evidence outlined above, the variant was classified as uncertain significance.