ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 26
Download table as spreadsheet
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 2021-02-22 criteria provided, single submitter clinical testing The p.Asp444His variant in BTD has been reported in several individuals with biotinidase deficiency, segregated with disease in affected relatives, and is predicted to lead to a ~25% reduction in biotinidase activity (Norrgard 1998 PMID: 9232193). It has also been identified in 5.55% (1396/25118) of Finnish chromosomes, including 53 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). Although this variant is seen in the general population, its frequency is consistent with its predicted effect. Individuals homozygous for the p.Asp444His variant are expected to have approximately 50% of mean normal serum biotinidase deficiency, similar to the activity of heterozygotes for profound biotinidase deficiency. When found in the compound heterozygous state with a severe pathogenic variant in BTD, this variant is reported to be the most common cause of partial biotinidase deficiency (Swango 1998 PMID: 9654207). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 1900). In vitro functional studies support an impact on protein function (Borsatto 2019 PMID: 31337602, Liu 2018 PMID: 29359854). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive biotinidase deficiency, though it is considered a mild allele. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong, PS3_Supporting.
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 RCV000001977 SCV000602894 pathogenic Biotinidase deficiency 2020-08-25 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% (9005/282830 alleles, including 199 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 2020-01-18 criteria provided, single submitter clinical testing Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on 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. Assessment of experimental evidence suggests this variant results in abnormal protein function.
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.
Mendelics RCV000001977 SCV001136347 pathogenic Biotinidase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001977 SCV001363363 pathogenic Biotinidase deficiency 2021-04-21 criteria provided, single submitter clinical testing Variant summary: BTD c.1270G>C (p.Asp424His), also known as c.1330G>C (p.Asp444His), results in a non-conservative amino acid change located in the Domain B (biotin-binding, Borsatto_2019) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.032 in 251430 control chromosomes in the gnomAD database, including 183 homozygotes. The observed variant frequency is significantly higher than estimated for a pathogenic variant in BTD causing Biotinidase Deficiency phenotype, suggesting that the variant is benign. c.1270G>C has been reported in the literature in multiple individuals affected with partial Biotinidase deficiency, a milder form of Biotinidase deficiency that is amenable to treatment with biotin (example, Swango_1998, Wiltink_2016, Procter_2016, Yilmaz_2018). Many of the patients presenting with partial Biotinidase deficiency attributed to this variant (c.1270G>C) were compound heterozygous with other BTD variants associated with a mild or a severe phenotype. However, this variant has also been observed in reportedly normal homozygous individuals who had >30% of wild-type levels of serum Biotinidase enzyme activity (Wiltink_2016). Since serum Biotinidase activity levels >30% are considered normal (Wiltnik_2016), these findings imply that homozygotes for this variant will be unaffected, a finding that is consistent with the high frequency of homozygotes in gnomAD database. c.1270G>C has also been observed in cis with p.Ala151Thr (also known as p.Ala171Thr) forming a complex allele that causes less than 10% of mean normal activity or profound Biotinidase deficiency in that allele (PMID: 10206677, Swango_1998, Wiltink_2016). Multiple publications report experimental evidence evaluating an impact on protein function. One study reported that this variant results in decreased protein expression but does not alter the activity of BTD enzyme (Liu_2018). Another study reports 46% of wild-type activity in cell homogenates but not in culture medium suggestive of an effect on enzyme lability rather than enzyme activity (Borsatto_2019). It is unclear how a 46% activity in cell homogenates correlates with a >30% activity in serum, which is considered normal. The authors state that the mechanism of decreased activity for this variant remains speculative (Borsatto_2019). Twenty ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely pathogenic (n=1) and pathogenic (n=17). Based on the evidence outlined above, the variant was classified as pathogenic in association with the phenotype of partial Biotinidase deficiency, a condition that is actionable and amenable to treatment with biotin.
Elsea Laboratory,Baylor College of Medicine RCV000001977 SCV001424287 uncertain significance Biotinidase deficiency 2020-04-01 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000001977 SCV001424378 pathogenic Biotinidase deficiency criteria provided, single submitter clinical testing
New York Genome Center RCV001263308 SCV001441349 pathogenic Global developmental delay; Seizures 2020-04-07 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000078064 SCV001448178 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000001977 SCV001449017 pathogenic Biotinidase deficiency 2018-09-13 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000001977 SCV001716385 pathogenic Biotinidase deficiency 2021-05-18 criteria provided, single submitter clinical testing
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
GenomeConnect, ClinGen RCV000001977 SCV001423160 not provided Biotinidase deficiency no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 12-12-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000001977 SCV001469294 pathogenic Biotinidase deficiency 2020-10-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000078064 SCV001551792 pathogenic not provided no assertion criteria provided clinical testing The BTD p.Asp444His variant is a well-known variant that causes partial Biotinidase (BTD) Deficiency (10-30% of normal enzyme activity) when found in the compound heterozygous state with a severe BTD mutation (Hymes_2001_PMID: 11668630). In addition, when the D444H variant is found on the same allele as A171T (double mutant), it is considered a pathogenic allele and can lead to profound BTD deficiency when found in the compound heterozygous state with another pathogenic allele (Norrgard_1998_PMID: 10206677). The variant was identified in dbSNP (ID: rs13078881), ClinVar (reported as pathogenic (11x), likely pathogenic (1x) and uncertain significance (1x)), Clinvitae and LOVD 3.0, but was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 9005 of 282830 chromosomes (199 homozygous) at a frequency of 0.031839 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 1396 of 25118 chromosomes (freq: 0.05558), European (non-Finnish) in 5119 of 129150 chromosomes (freq: 0.03964), South Asian in 1129 of 30616 chromosomes (freq: 0.03688), Ashkenazi Jewish in 340 of 10368 chromosomes (freq: 0.03279), Other in 217 of 7222 chromosomes (freq: 0.03005), Latino in 643 of 35436 chromosomes (freq: 0.01815), African in 159 of 24966 chromosomes (freq: 0.006369), and East Asian in 2 of 19954 chromosomes (freq: 0.0001). Liu et al. (2018) recently found that the D444H variant results in a decrease in protein expression with no loss of enzyme activity (Liu_2018_PMID: 29359854). Other studies have found 50% of normal BTD enzyme activity with one D444H allele present 25% activity with two D444H alleles present (Cowan_2010_PMID: 20539236), therefore indicating the effect of this variant on the protein. In summary, this variant is considered a hypomorphic allele and in combination with other variants in cis or trans, may result in reduced enzyme activity. Based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.