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: 39688110, 14707518, 15060693)
NM_001370658.1(BTD):c.176G>A (p.Arg59His)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
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: VCV000038567.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
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 15, 2026 Aug 26, 2025 - HGVS
-
... 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
-
R79H
- Canonical SPDI
- NC_000003.12:15635614:G:A
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
791 | 981 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 8, 2025 | RCV000021905.31 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 26, 2025 | RCV003125847.9 |
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Biotinidase deficiency
(Autosomal recessive inheritance)
|
Suma Genomics
Accession: SCV002543789.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: inherited
Affected status: yes
Test name: Exome sequencing
Platform type: Next Generation Sequencing
|
|
|
Likely pathogenic
(Aug 22, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Biotinidase deficiency |
Baylor Genetics
Accession: SCV004211432.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Likely pathogenic
(Aug 26, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV003803151.2
First in ClinVar: Feb 18, 2023 Last updated: Sep 06, 2025 |
Comment:
show
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: 39688110, 14707518, 15060693) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jul 08, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Biotinidase deficiency |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813838.3
First in ClinVar: Apr 15, 2024 Last updated: Nov 02, 2025 |
Comment:
show
Variant summary: BTD c.176G>A (p.Arg59His), also reported as NM_000060.3:c.236G>A p.Arg79His, results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.176G>A has been observed in trans with a null pathogenic frameshift in at least 1 individual(s) affected with Biotinidase Deficiency (Laszlo_2003). Further, a different missense variant at the same codon (c.175C>T, p.Arg59Cys) has been determined to be likely pathogenic/pathogenic by our laboratory, supporting the critical relevance of codon 59 for BTD protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in patient sample(s) (Laszlo_2003). ClinVar contains an entry for this variant (Variation ID: 38567). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 02, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Biotinidase deficiency |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001411319.7
First in ClinVar: Jul 16, 2020 Last updated: Feb 15, 2026 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(Sep 16, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Biotinidase deficiency |
Natera, Inc.
Accession: SCV002081545.2
First in ClinVar: Apr 23, 2022 Last updated: Jun 08, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Nov 14, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Biotinidase deficiency |
Counsyl
Accession: SCV000800614.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
Comment:
Comment:
Variant summary: BTD c.176G>A (p.Arg59His), also reported as NM_000060.3:c.236G>A p.Arg79His, results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes. c.176G>A has been observed in trans with a null pathogenic frameshift in at least 1 individual(s) affected with Biotinidase Deficiency (Laszlo_2003). Further, a different missense variant at the same codon (c.175C>T, p.Arg59Cys) has been determined to be likely pathogenic/pathogenic by our laboratory, supporting the critical relevance of codon 59 for BTD protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in patient sample(s) (Laszlo_2003). ClinVar contains an entry for this variant (Variation ID: 38567). Based on the evidence outlined above, the variant was classified as pathogenic.
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.
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
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 Apr 18, 2026
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.