This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 424 of the BTD protein (p.Cys424Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 15776412, 29359854). ClinVar contains an entry for this variant (Variation ID: 1675907). 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%. Experimental studies have shown that this missense change affects BTD function (PMID: 29359854). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.1211G>C (p.Cys404Ser)
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.
(4)
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.
Pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001370658.1(BTD):c.1211G>C (p.Cys404Ser)
Variation ID: 1675907 Accession: VCV001675907.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.1 3: 15645127 (GRCh38) [ NCBI UCSC ] 3: 15686634 (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 8, 2022 Oct 20, 2024 Apr 17, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370658.1:c.1211G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Cys404Ser missense NM_000060.4:c.1271G>C NP_000051.1:p.Cys424Ser missense NM_001281723.4:c.1211G>C NP_001268652.2:p.Cys404Ser missense NM_001281724.3:c.1211G>C NP_001268653.2:p.Cys404Ser missense NM_001281725.3:c.1211G>C NP_001268654.1:p.Cys404Ser missense NM_001323582.2:c.1211G>C NP_001310511.1:p.Cys404Ser missense NM_001370752.1:c.1015+196G>C intron variant NM_001370753.1:c.399+3070G>C intron variant NM_001407364.1:c.1211G>C NP_001394293.1:p.Cys404Ser missense NM_001407365.1:c.1211G>C NP_001394294.1:p.Cys404Ser missense NM_001407366.1:c.1211G>C NP_001394295.1:p.Cys404Ser missense NM_001407367.1:c.1211G>C NP_001394296.1:p.Cys404Ser missense NM_001407368.1:c.1211G>C NP_001394297.1:p.Cys404Ser missense NM_001407369.1:c.1211G>C NP_001394298.1:p.Cys404Ser missense NM_001407370.1:c.1211G>C NP_001394299.1:p.Cys404Ser missense NM_001407371.1:c.1211G>C NP_001394300.1:p.Cys404Ser missense NM_001407372.1:c.1211G>C NP_001394301.1:p.Cys404Ser missense NM_001407373.1:c.1211G>C NP_001394302.1:p.Cys404Ser missense NM_001407374.1:c.1211G>C NP_001394303.1:p.Cys404Ser missense NM_001407375.1:c.1211G>C NP_001394304.1:p.Cys404Ser missense NM_001407376.1:c.1211G>C NP_001394305.1:p.Cys404Ser missense NM_001407377.1:c.1211G>C NP_001394306.1:p.Cys404Ser missense NM_001407378.1:c.1211G>C NP_001394307.1:p.Cys404Ser missense NC_000003.12:g.15645127G>C NC_000003.11:g.15686634G>C NG_008019.2:g.48776G>C NG_008019.3:g.48777G>C - Protein change
- C404S
- Other names
- -
- Canonical SPDI
- NC_000003.12:15645126:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- 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 |
667 | 753 | |
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 (1) |
criteria provided, single submitter
|
Mar 1, 2022 | RCV002214276.19 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 17, 2024 | RCV003475304.4 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211482.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Dec 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293424.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 424 of the BTD protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 424 of the BTD protein (p.Cys424Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 15776412, 29359854). ClinVar contains an entry for this variant (Variation ID: 1675907). 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%. Experimental studies have shown that this missense change affects BTD function (PMID: 29359854). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005077652.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: BTD c.1211G>C (p.Cys404Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: BTD c.1211G>C (p.Cys404Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes (gnomAD). c.1211G>C has been reported in the literature in individuals affected with Biotinidase Deficiency (Wolf_2005, Lui_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a complete loss of BTD activity (Lui_2018). The following publications have been ascertained in the context of this evaluation (PMID: 15776412, 29359854). ClinVar contains an entry for this variant (Variation ID: 1675907). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002496791.18
First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024 |
Comment:
BTD: PS3, PM1, PM2, PM5, PS4:Moderate, PP3
Number of individuals with the variant: 1
|
Comment:
Comment:
Variant summary: BTD c.1211G>C (p.Cys404Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes (gnomAD). c.1211G>C has been reported in the literature in individuals affected with Biotinidase Deficiency (Wolf_2005, Lui_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a complete loss of BTD activity (Lui_2018). The following publications have been ascertained in the context of this evaluation (PMID: 15776412, 29359854). ClinVar contains an entry for this variant (Variation ID: 1675907). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
BTD: PS3, PM1, PM2, PM5, PS4:Moderate, PP3
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 cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 424 of the BTD protein (p.Cys424Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 15776412, 29359854). ClinVar contains an entry for this variant (Variation ID: 1675907). 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%. Experimental studies have shown that this missense change affects BTD function (PMID: 29359854). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: BTD c.1211G>C (p.Cys404Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes (gnomAD). c.1211G>C has been reported in the literature in individuals affected with Biotinidase Deficiency (Wolf_2005, Lui_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a complete loss of BTD activity (Lui_2018). The following publications have been ascertained in the context of this evaluation (PMID: 15776412, 29359854). ClinVar contains an entry for this variant (Variation ID: 1675907). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
BTD: PS3, PM1, PM2, PM5, PS4:Moderate, PP3
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 |
| Biotinidase deficiency: novel mutations and their biochemical and clinical correlates. | Wolf B | Human mutation | 2005 | PMID: 15776412 |
Text-mined citations for rs397514335 ...
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 20, 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.