ClinVar Miner

Submissions for variant NM_001370658.1(BTD):c.1270G>C (p.Asp424His) (rs13078881)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001977 SCV000220789 pathogenic Biotinidase deficiency 2014-10-13 criteria provided, single submitter literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000001977 SCV000221176 pathogenic Biotinidase deficiency 2013-11-09 criteria provided, single submitter clinical testing The p.Asp444His variant in BTD has been previously identified in several individ uals with biotinidase deficiency and is predicted to lead to a ~25% reduction in biotinidase activity (Norrgard 1998). This variant has also been identified in 5.5% (1422/25788) of Finnish chromosomes by the Genome Aggregation Database (gno mAD, http://gnomad.broadinstitute.org; dbSNP rs13078881). Although this variant is seen in the general population, its frequency is consistent with its predicte d effect. Individuals homozygous for the p.Asp444His variant are expected to ha ve approximately 50% of mean normal serum biotinidase deficiency, similar to the activity of heterozygotes for profound biotinidase deficiency. In summary, this variant meets our criteria to be classified as pathogenic for biotinidase defic iency in an autosomal recessive manner based upon its segregation in affected in dividuals and functional evidence, though it is considered a mild pathogenic all ele. ACMG/AMP Criteria applied: PS3, PM3 (upgraded to Strong based on multiple o ccurrences), PP5 .
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078064 SCV000230009 pathogenic not provided 2016-06-20 criteria provided, single submitter clinical testing
GeneDx RCV000078064 SCV000238750 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The D444H pathogenic variant in the BTD gene has been reported previously in association with biotinidase deficiency (Norrgard et al., 1998). One D444H variant in combination with a pathogenic variant for profound deficiency on the other allele is the predominant cause of partial biotinidase deficiency (Hymes et al., 2001).
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078064 SCV000281098 pathogenic not provided 2015-02-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000001977 SCV000593789 pathogenic Biotinidase deficiency 2016-04-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000078064 SCV000602894 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing The BTD c.1330G>C; p.Asp444His variant (rs13078881) is reported in multiple patients with partial biotinidase deficiency (Dobrowolski 2003, Funghini 2002, Milankovics 2010, Muhl 2001, Pomponio 2000, Swango 1998, Wolf 2005), with a higher prevalence in affected individuals (Milankovics 2010). This variant is reported multiple times in the ClinVar database as pathogenic (Variation ID: 1900), and found in the general population with an overall allele frequency of 3.2% (8916/277178 alleles, including 198 homozygotes) in the Genome Aggregation Database. The aspartate at codon 444 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that the variant is deleterious. Based on available information, this variant is considered to be mildly pathogenic. REFERENCES Dobrowolski S et al. Real time PCR assays to detect common mutations in the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency. Mol Genet Metab. 2003 Feb;78(2):100-7. Funghini S et al. Two new mutations in children affected by partial biotinidase deficiency ascertained by newborn screening. J Inherit Metab Dis. 2002 Aug;25(4):328-30. Milankovics I et al. High frequencies of biotinidase (BTD) gene mutations in the Hungarian population. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S289-92. Muhl A et al. Molecular characterisation of 34 patients with biotinidase deficiency ascertained by newborn screening and family investigation. Eur J Hum Genet. 2001 Apr;9(4):237-43. Pomponio R et al. Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis. 2000 Mar;23(2):120-8. Swango K et al. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet. 1998 May;102(5):571-5. Wolf B et al. Biotinidase deficiency: novel mutations and their biochemical and clinical correlates. Hum Mutat. 2005 Apr;25(4):413.
Fulgent Genetics,Fulgent Genetics RCV000001977 SCV000611182 likely pathogenic Biotinidase deficiency 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000001977 SCV000630324 pathogenic Biotinidase deficiency 2018-07-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 444 of the BTD protein (p.Asp444His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs13078881, ExAC 5%). In the homozygous state this variant does not cause biotinidase deficiency or partial biotinidase deficiency (PMID: 28682309, 9654207). However, this variant in conjunction with another pathogenic variant is a common cause of partial biotinidase deficiency (PMID: 10206677, 9654207, 12227467, 23644139). This variant has also been observed in individuals affected with profound biotinidase deficiency when this variant is in cis with the p.A171T variant and in trans with a third variant (PMID: 10206677, 9654207). ClinVar contains an entry for this variant (Variation ID: 16939). In individuals affected with partial biotinidase deficiency who harbor this variant in combination with another BTD variant, serum biotinidase activity was approximately 24% of the mean normal control activity (PMID: 9654207). In individuals affected with profound biotinidase deficiency who harbor this variant in cis with p.A171T and in trans with another BTD variant, serum biotinidase activity was <10% of the mean normal control activity (PMID: 10206677, 9654207). Individuals who are homozygous for this variant typically have an enzyme activity that is approximately 50% of normal (PMID: 20539236, 28682309, 9654207), similar to what is seen for heterozygous carriers of a profound allele. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078064 SCV000888008 pathogenic not provided 2016-01-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000001977 SCV000915028 pathogenic Biotinidase deficiency 2017-04-27 criteria provided, single submitter clinical testing The BTD c.1330G>C (p.Asp444His) variant has been reported as the most common variant found in newborns screened for profound biotinidase deficiency. However, in individuals with profound biotinidase deficiency, the variant is usually found in cis with one of three additional variants (Norrgard et al. 1999). In the studies by Norrgard et al. (1998; 1999), 14 of 31 children with biotinidase deficiency carried both the p.Asp444His and the p.Ala171Thr variants in cis. This double variant allele has been identified as the second most common allele in newborns screened for biotinidase deficiency. The combination of the two variants resulted in approximately 52% enzyme loss. In control populations, 23 of 296 healthy individuals were identified with the p.Asp444His variant versus none of 376 with the p.Ala171Thr variant. The p.Asp444His variant alone is reported to be the most common cause of partial biotinidase deficiency (10% to 30% of normal serum activity) when found in a compound heterozygous state with a severe pathogenic variant in the BTD gene (Swango et al. 1998). Individuals who are homozygous for the p.Asp444His variant have approximately 50% of mean normal enzyme activity (Pindolia et al. 2010). Untreated individuals with partial biotinidase deficiency are often asymptomatic in the absence of confounding factors such as significant illness. The p.Asp444His variant is reported at a frequency of 0.0758 in the Finnish population of the 1000 Genomes Project. Although this allele frequency appears inconsistent with the disease prevalence, the p.Asp444His variant appears to be a mild variant when found in trans with a severe pathogenic variant, and is only associated with severe biotinidase deficiency when found in cis with a more severe variant and in trans with a severe pathogenic variant. Based on the evidence, the p.Asp444His variant is classified as pathogenic for biotinidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneReviews RCV000001977 SCV000040402 pathologic Biotinidase deficiency 2011-03-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Research and Development, ARUP Laboratories RCV000001977 SCV000042676 pathogenic Biotinidase deficiency 2017-02-17 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000001977 SCV000536695 pathogenic Biotinidase deficiency 2016-06-10 no assertion criteria provided research
SingHealth Duke-NUS Institute of Precision Medicine RCV000001977 SCV000853151 uncertain significance Biotinidase deficiency 2017-06-07 no assertion criteria provided curation

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