This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 195 of the BTD protein (p.Asn195Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, 11865279). ClinVar contains an entry for this variant (Variation ID: 25021). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Asn195 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 17185019), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.523A>G (p.Asn175Asp)
Germline
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.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(2)
Pathogenic(1); Likely pathogenic(1); Uncertain significance(2)
5
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001370658.1(BTD):c.523A>G (p.Asn175Asp)
Variation ID: 25021 Accession: VCV000025021.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644439 (GRCh38) [ NCBI UCSC ] 3: 15685946 (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 14, 2024 Sep 27, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370658.1:c.523A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Asn175Asp missense NM_000060.4:c.583A>G NP_000051.1:p.Asn195Asp missense NM_001281723.4:c.523A>G NP_001268652.2:p.Asn175Asp missense NM_001281724.3:c.523A>G NP_001268653.2:p.Asn175Asp missense NM_001281725.3:c.523A>G NP_001268654.1:p.Asn175Asp missense NM_001323582.2:c.523A>G NP_001310511.1:p.Asn175Asp missense NM_001370752.1:c.523A>G NP_001357681.1:p.Asn175Asp missense NM_001370753.1:c.399+2382A>G intron variant NM_001407364.1:c.523A>G NP_001394293.1:p.Asn175Asp missense NM_001407365.1:c.523A>G NP_001394294.1:p.Asn175Asp missense NM_001407366.1:c.523A>G NP_001394295.1:p.Asn175Asp missense NM_001407367.1:c.523A>G NP_001394296.1:p.Asn175Asp missense NM_001407368.1:c.523A>G NP_001394297.1:p.Asn175Asp missense NM_001407369.1:c.523A>G NP_001394298.1:p.Asn175Asp missense NM_001407370.1:c.523A>G NP_001394299.1:p.Asn175Asp missense NM_001407371.1:c.523A>G NP_001394300.1:p.Asn175Asp missense NM_001407372.1:c.523A>G NP_001394301.1:p.Asn175Asp missense NM_001407373.1:c.523A>G NP_001394302.1:p.Asn175Asp missense NM_001407374.1:c.523A>G NP_001394303.1:p.Asn175Asp missense NM_001407375.1:c.523A>G NP_001394304.1:p.Asn175Asp missense NM_001407376.1:c.523A>G NP_001394305.1:p.Asn175Asp missense NM_001407377.1:c.523A>G NP_001394306.1:p.Asn175Asp missense NM_001407378.1:c.523A>G NP_001394307.1:p.Asn175Asp missense NM_001407379.1:c.523A>G NP_001394308.1:p.Asn175Asp missense NC_000003.12:g.15644439A>G NC_000003.11:g.15685946A>G NG_008019.2:g.48088A>G NG_008019.3:g.48089A>G - Protein change
- N175D
- Other names
- -
- Canonical SPDI
- NC_000003.12:15644438:A:G
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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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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 | - | - |
GRCh38 GRCh37 |
670 | 756 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Apr 16, 2022 | RCV000021942.14 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 3, 2018 | RCV000727575.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 27, 2022 | RCV002298448.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jul 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800562.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
|
|
Pathogenic
(Apr 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001391009.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 195 of the BTD protein … (more)
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 195 of the BTD protein (p.Asn195Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, 11865279). ClinVar contains an entry for this variant (Variation ID: 25021). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Asn195 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 17185019), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Jan 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854816.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Uncertain significance
(Sep 27, 2022)
|
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: SCV002598711.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: BTD c.523A>G (p.Asn175Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: BTD c.523A>G (p.Asn175Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.523A>G has been reported in the literature in an individual affected with Biotinidase Deficiency (example: Pomponio_1997). This information is insufficient to allow any conclusion about the variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
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Pathogenic
(Apr 20, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081555.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Variant summary: BTD c.523A>G (p.Asn175Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.523A>G has been reported in the literature in an individual affected with Biotinidase Deficiency (example: Pomponio_1997). This information is insufficient to allow any conclusion about the variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 195 of the BTD protein (p.Asn195Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, 11865279). ClinVar contains an entry for this variant (Variation ID: 25021). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Asn195 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 17185019), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: BTD c.523A>G (p.Asn175Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.523A>G has been reported in the literature in an individual affected with Biotinidase Deficiency (example: Pomponio_1997). This information is insufficient to allow any conclusion about the variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutations causing biotinidase deficiency in children ascertained by newborn screening in Western Hungary. | Milánkovics I | Molecular genetics and metabolism | 2007 | PMID: 17185019 |
| Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. | Wolf B | The Journal of pediatrics | 2002 | PMID: 11865279 |
| Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. | Pomponio RJ | Pediatric research | 1997 | PMID: 9396567 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BTD | - | - | - | - |
Text-mined citations for rs397514370 ...
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 Oct 08, 2024
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.