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)
ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.176G>A (p.Arg59His)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
5 out of 7 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
7
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001370658.1(BTD):c.176G>A (p.Arg59His)
Variation ID: 38567 Accession: VCV000038567.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15635615 (GRCh38) [ NCBI UCSC ] 3: 15677122 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 25, 2025 Aug 2, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370658.1:c.176G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Arg59His missense NM_000060.4:c.236G>A NP_000051.1:p.Arg79His missense NM_001281723.4:c.176G>A NP_001268652.2:p.Arg59His missense NM_001281724.3:c.176G>A NP_001268653.2:p.Arg59His missense NM_001281725.3:c.176G>A NP_001268654.1:p.Arg59His missense NM_001281726.3:c.176G>A NP_001268655.2:p.Arg59His missense NM_001323582.2:c.176G>A NP_001310511.1:p.Arg59His missense NM_001370752.1:c.176G>A NP_001357681.1:p.Arg59His missense NM_001370753.1:c.176G>A NP_001357682.1:p.Arg59His missense NM_001407364.1:c.176G>A NP_001394293.1:p.Arg59His missense NM_001407365.1:c.176G>A NP_001394294.1:p.Arg59His missense NM_001407366.1:c.176G>A NP_001394295.1:p.Arg59His missense NM_001407367.1:c.176G>A NP_001394296.1:p.Arg59His missense NM_001407368.1:c.176G>A NP_001394297.1:p.Arg59His missense NM_001407369.1:c.176G>A NP_001394298.1:p.Arg59His missense NM_001407370.1:c.176G>A NP_001394299.1:p.Arg59His missense NM_001407371.1:c.176G>A NP_001394300.1:p.Arg59His missense NM_001407372.1:c.176G>A NP_001394301.1:p.Arg59His missense NM_001407373.1:c.176G>A NP_001394302.1:p.Arg59His missense NM_001407374.1:c.176G>A NP_001394303.1:p.Arg59His missense NM_001407375.1:c.176G>A NP_001394304.1:p.Arg59His missense NM_001407376.1:c.176G>A NP_001394305.1:p.Arg59His missense NM_001407377.1:c.176G>A NP_001394306.1:p.Arg59His missense NM_001407378.1:c.176G>A NP_001394307.1:p.Arg59His missense NM_001407379.1:c.176G>A NP_001394308.1:p.Arg59His missense NM_001407380.1:c.176G>A NP_001394309.1:p.Arg59His missense NM_001407381.1:c.176G>A NP_001394310.1:p.Arg59His missense NM_001407382.1:c.176G>A NP_001394311.1:p.Arg59His missense NM_001407383.1:c.176G>A NP_001394312.1:p.Arg59His missense NM_001407384.1:c.176G>A NP_001394313.1:p.Arg59His missense NM_001407386.1:c.176G>A NP_001394315.1:p.Arg59His missense NM_001407388.1:c.176G>A NP_001394317.1:p.Arg59His missense NM_001407390.1:c.176G>A NP_001394319.1:p.Arg59His missense NM_001407392.1:c.176G>A NP_001394321.1:p.Arg59His missense NM_001407394.1:c.176G>A NP_001394323.1:p.Arg59His missense NM_001407395.1:c.176G>A NP_001394324.1:p.Arg59His missense NM_001407396.1:c.176G>A NP_001394325.1:p.Arg59His missense NM_001407397.1:c.176G>A NP_001394326.1:p.Arg59His missense NM_001407398.1:c.176G>A NP_001394327.1:p.Arg59His missense NM_001407399.1:c.176G>A NP_001394328.1:p.Arg59His missense NM_001407400.1:c.176G>A NP_001394329.1:p.Arg59His missense NM_001407401.1:c.176G>A NP_001394330.1:p.Arg59His missense NC_000003.12:g.15635615G>A NC_000003.11:g.15677122G>A NG_008019.2:g.39264G>A - Protein change
- R59H
- Other names
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R79H
- Canonical SPDI
- NC_000003.12:15635614:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BTD | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh37 |
710 | 809 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 2, 2024 | RCV000021905.27 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 12, 2024 | RCV003993755.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 14, 2022 | RCV003125847.8 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
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Likely pathogenic
(Aug 22, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211432.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Suma Genomics
Accession: SCV002543789.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Likely pathogenic
(Jul 14, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003803151.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
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; … (more)
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) (less)
|
|
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Uncertain significance
(Feb 12, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813838.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Aug 02, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001411319.6
First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025 |
Comment:
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). … (more)
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 with a positive predictive value of 95%. 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. (less)
|
|
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Likely pathogenic
(Sep 09, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081545.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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Uncertain significance
(Nov 14, 2017)
N
Not contributing to aggregate classification
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800614.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
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.
Comment:
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 with a positive predictive value of 95%. 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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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.
Comment:
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 with a positive predictive value of 95%. 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical features, BTD gene mutations, and their functional studies of eight symptomatic patients with biotinidase deficiency from Southern China. | Liu Z | American journal of medical genetics. Part A | 2018 | PMID: 29359854 |
| Clinical, Biochemical and Genetic Analysis of Biotinidase Deficiency in Iranian Population. | Asgari A | Archives of Iranian medicine | 2016 | PMID: 27845546 |
| Mutations causing biotinidase deficiency in children ascertained by newborn screening in Western Hungary. | Milánkovics I | Molecular genetics and metabolism | 2007 | PMID: 17185019 |
| Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. | Neto EC | Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas | 2004 | PMID: 15060693 |
| Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. | László A | Journal of inherited metabolic disease | 2003 | PMID: 14707518 |
| Novel mutations cause biotinidase deficiency in Turkish children. | Pomponio RJ | Journal of inherited metabolic disease | 2000 | PMID: 10801053 |
Text-mined citations for rs397514343 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Mar 16, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.