Submissions for variant NM_001370658.1(BTD):c.176G>A (p.Arg59His)

gnomAD frequency: 0.00001  dbSNP: rs397514343

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021905	SCV001411319	pathogenic	Biotinidase deficiency	2023-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 79 of the BTD protein (p.Arg79His). This variant is present in population databases (rs397514343, gnomAD 0.003%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 14707518). 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: 38567). 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. This variant disrupts the p.Arg79 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10801053, 15060693, 27845546, 29359854). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Suma Genomics	RCV000021905	SCV002543789	pathogenic	Biotinidase deficiency		criteria provided, single submitter	clinical testing
GeneDx	RCV003125847	SCV003803151	likely pathogenic	not provided	2022-07-14	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; Also known as c.236 G>A (79 R>H); This variant is associated with the following publications: (PMID: 14707518, 15060693)
Baylor Genetics	RCV000021905	SCV004211432	likely pathogenic	Biotinidase deficiency	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993755	SCV004813838	uncertain significance	not specified	2024-02-12	criteria provided, single submitter	clinical testing	Variant summary: BTD c.176G>A (p.Arg59His) 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 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.176G>A has been reported in the literature in at least one compound heterozygous individual affected with Biotinidase Deficiency (Laszlo_2003). These data do not allow any conclusion about variant significance. Other variants at the Arg59 residue have been reported as associated with disease (p.Arg59Cys), suggesting that this codon is functionally important. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 38567). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000021905	SCV000800614	uncertain significance	Biotinidase deficiency	2017-11-14	flagged submission	clinical testing
Natera, Inc.	RCV000021905	SCV002081545	likely pathogenic	Biotinidase deficiency	2020-09-09	no assertion criteria provided	clinical testing