VCV000038567.18 - ClinVar

NM_001370658.1(BTD):c.176G>A (p.Arg59His)

Germline

Classification

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)

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(2); Likely pathogenic(2); Uncertain significance(1)

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.176G>A (p.Arg59His)

Variation ID: 38567 Accession: VCV000038567.18

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	Apr 15, 2024	Feb 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

R59H

Other names

R79H

Canonical SPDI

NC_000003.12:15635614:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs397514343 ClinGen: CA278166 VarSome

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
Gene	OMIM	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.
Biotinidase deficiency	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 24, 2023	RCV000021905.25
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jul 14, 2022	RCV003125847.8
not specified	Uncertain significance (1)	criteria provided, single submitter	Feb 12, 2024	RCV003993755.1

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.
Likely pathogenic (Aug 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) 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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Biotinidase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Suma Genomics, Suma Genomics Accession: SCV002543789.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Likely pathogenic (Jul 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) 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)
Pathogenic (Sep 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Biotinidase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001411319.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 14707518‚ 10801053‚ 15060693‚ 27845546‚ 29359854 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. 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)
Uncertain significance (Feb 12, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) 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	Publications: PubMed (1) PubMed: 14707518 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)
Likely pathogenic (Sep 09, 2020)	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
Uncertain significance (Nov 14, 2017)	Flagged submission flagged submission (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) 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	Publications: PubMed (3) PubMed: 17185019‚ 15060693‚ 14707518
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

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:

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. 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:

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.

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:

Citations for germline classification of this variant

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 ...

These 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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_001370658.1(BTD):c.176G>A (p.Arg59His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397514343 ...