ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.468G>T (p.Lys156Asn) (rs397514367)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078074 SCV000230011 pathogenic not provided 2016-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000078074 SCV000490442 pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing The K176N pathogenic variant was identified in approximately 72% of alleles in Hispanic BTD patients, and is associated with profound biotinidase deficiency (Cowan et al. 2012; Norrgard et al. 1999). The K176N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret K176N as a pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078074 SCV000600943 pathogenic not provided 2020-09-09 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Invitae RCV000021938 SCV000630335 pathogenic Biotinidase deficiency 2018-05-22 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 176 of the BTD protein (p.Lys176Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs397514367, ExAC 0.03%). This variant is a prevalent BTD deficiency allele in the Hispanic population (PMID: 22698809). It has been reported as homozygous or in combination with another BTD variant in multiple individuals affected with profound biotinidase deficiency (<10% normal activity) as well as in two asymptomatic individuals identified through newborn screening (PMID: 22698809, 10400129). ClinVar contains an entry for this variant (Variation ID: 25018). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000623242 SCV000743079 pathogenic Inborn genetic diseases 2017-11-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000021938 SCV001158622 pathogenic Biotinidase deficiency 2019-11-04 criteria provided, single submitter clinical testing The BTD c.528G>T; p.Lys176Asn variant (rs397514367) is reported in the literature in the homozygous or compound heterozygous state in multiple Hispanic individuals affected with biotinidase deficiency (Cowan 2012, Norrgard 1999, Procter 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 25018). It is found in the Latino population with an allele frequency of 0.074% (26/35434 alleles) in the Genome Aggregation Database. The lysine at codon 176 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Cowan TM et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug;106(4):485-7. Norrgard K et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res 1999 46(1):20-7. Procter M et al. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab. 2016 Mar;117(3):369-72.
Research and Development, ARUP Laboratories RCV000021938 SCV000042607 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only
Counsyl RCV000021938 SCV000485686 likely pathogenic Biotinidase deficiency 2016-06-20 no assertion criteria provided clinical testing
Natera, Inc. RCV000021938 SCV001460183 pathogenic Biotinidase deficiency 2020-09-16 no assertion criteria provided clinical testing

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