Submissions for variant NM_001370658.1(BTD):c.604G>A (p.Asp202Asn)

gnomAD frequency: 0.00003  dbSNP: rs200337373

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420327	SCV000521149	likely benign	not provided	2021-05-07	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: 31337602, 25174816, 27378695)
Counsyl	RCV000675128	SCV000800698	uncertain significance	Biotinidase deficiency	2018-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731677	SCV001983546	likely benign	not specified	2021-09-28	criteria provided, single submitter	clinical testing	Variant summary: BTD c.604G>A (p.Asp202Asn) results in a conservative amino acid change located in the Nitrilase/Amidase homologous domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 273024 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00011 vs 0.0046), allowing no conclusion about variant significance. c.604G>A has been reported in the literature in individuals affected with Biotinidase Deficiency (Borsatto_2014) or Ovarian Cancer (Permuth_2016). These reports do not provide unequivocal conclusions about association of the variant with Biotinidase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Borsatto_2019). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675128	SCV003266312	uncertain significance	Biotinidase deficiency	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 222 of the BTD protein (p.Asp222Asn). This variant is present in population databases (rs200337373, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 25174816, 28498829). ClinVar contains an entry for this variant (Variation ID: 381650). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BTD function (PMID: 31337602). This variant disrupts the p.Asp222 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 22698809, 26810761), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004022351	SCV004915851	uncertain significance	Inborn genetic diseases	2022-05-10	criteria provided, single submitter	clinical testing	The c.664G>A (p.D222N) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a G to A substitution at nucleotide position 664, causing the aspartic acid (D) at amino acid position 222 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251699	SCV001427440	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing