VCV001330018.4 - ClinVar

NM_001370658.1(BTD):c.1036_1037dup (p.Gly347fs)

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.

(3)

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

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.1036_1037dup (p.Gly347fs)

Variation ID: 1330018 Accession: VCV001330018.4

Type and length

Duplication, 2 bp

Location

Cytogenetic: 3p25.1 3: 15644951-15644952 (GRCh38) [ NCBI UCSC ] 3: 15686458-15686459 (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	Jan 3, 2022	Feb 14, 2024	Sep 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001370658.1:c.1036_1037dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001357587.1:p.Gly347fs	frameshift
NM_000060.4:c.1096_1097dup	NP_000051.1:p.Gly367Glnfs	frameshift
NM_001281723.4:c.1036_1037dup	NP_001268652.2:p.Gly347Glnfs	frameshift
NM_001281724.3:c.1036_1037dup	NP_001268653.2:p.Gly347fs	frameshift
NM_001281725.3:c.1036_1037dup	NP_001268654.1:p.Gly347Glnfs	frameshift
NM_001323582.2:c.1036_1037dup	NP_001310511.1:p.Gly347Glnfs	frameshift
NM_001370752.1:c.1015+21_1015+22dup		intron variant
NM_001370753.1:c.399+2895_399+2896dup		intron variant
NM_001407364.1:c.1036_1037dup	NP_001394293.1:p.Gly347Glnfs	frameshift
NM_001407365.1:c.1036_1037dup	NP_001394294.1:p.Gly347Glnfs	frameshift
NM_001407366.1:c.1036_1037dup	NP_001394295.1:p.Gly347Glnfs	frameshift
NM_001407367.1:c.1036_1037dup	NP_001394296.1:p.Gly347Glnfs	frameshift
NM_001407368.1:c.1036_1037dup	NP_001394297.1:p.Gly347Glnfs	frameshift
NM_001407369.1:c.1036_1037dup	NP_001394298.1:p.Gly347Glnfs	frameshift
NM_001407370.1:c.1036_1037dup	NP_001394299.1:p.Gly347Glnfs	frameshift
NM_001407371.1:c.1036_1037dup	NP_001394300.1:p.Gly347Glnfs	frameshift
NM_001407372.1:c.1036_1037dup	NP_001394301.1:p.Gly347Glnfs	frameshift
NM_001407373.1:c.1036_1037dup	NP_001394302.1:p.Gly347Glnfs	frameshift
NM_001407374.1:c.1036_1037dup	NP_001394303.1:p.Gly347Glnfs	frameshift
NM_001407375.1:c.1036_1037dup	NP_001394304.1:p.Gly347Glnfs	frameshift
NM_001407376.1:c.1036_1037dup	NP_001394305.1:p.Gly347Glnfs	frameshift
NM_001407377.1:c.1036_1037dup	NP_001394306.1:p.Gly347Glnfs	frameshift
NM_001407378.1:c.1036_1037dup	NP_001394307.1:p.Gly347Glnfs	frameshift
NC_000003.12:g.15644952_15644953dup
NC_000003.11:g.15686459_15686460dup
NG_008019.2:g.48601_48602dup
NG_008019.3:g.48602_48603dup

... more HGVS ... less HGVS

Protein change

G347fs

Other names

Canonical SPDI

NC_000003.12:15644951:TC:TCTC

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

dbSNP: rs1004027979 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	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.
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 28, 2020	RCV001801035.2
Biotinidase deficiency	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 10, 2023	RCV003475096.3

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 (Oct 28, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002046342.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022	Publications: PubMed (1) PubMed: 26810761 Comment: The frameshift variant causes the premature termination of BTD protein synthesis. It has been reported in an individual with biotinidase deficiency in the published literature … (more) The frameshift variant causes the premature termination of BTD protein synthesis. It has been reported in an individual with biotinidase deficiency in the published literature (PMID: 26810761 (2016))). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic. (less)
Pathogenic (Jul 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Biotinidase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211439.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Sep 10, 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: SCV004293422.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 26810761‚ 17382128‚ 19728141‚ 29359854 Comment: This sequence change creates a premature translational stop signal (p.Gly367Glnfs23) in the BTD gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Gly367Glnfs23) in the BTD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the BTD protein. This variant is present in population databases (no rsID available, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with biotinidase deficiency (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 1330018). This variant disrupts a region of the BTD protein in which other variant(s) (p.Leu498Phefs*13) have been determined to be pathogenic (PMID: 17382128, 19728141, 29359854). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

The frameshift variant causes the premature termination of BTD protein synthesis. It has been reported in an individual with biotinidase deficiency in the published literature (PMID: 26810761 (2016))). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Gly367Glnfs*23) in the BTD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the BTD protein. This variant is present in population databases (no rsID available, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with biotinidase deficiency (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 1330018). This variant disrupts a region of the BTD protein in which other variant(s) (p.Leu498Phefs*13) have been determined to be pathogenic (PMID: 17382128, 19728141, 29359854). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it 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:

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
Forty-eight novel mutations causing biotinidase deficiency.	Procter M	Molecular genetics and metabolism	2016	PMID: 26810761
Diagnosis, treatment, follow-up and gene mutation analysis in four Chinese children with biotinidase deficiency.	Ye J	Journal of inherited metabolic disease	2009	PMID: 19728141
Hearing loss in biotinidase deficiency: genotype-phenotype correlation.	Sivri HS	The Journal of pediatrics	2007	PMID: 17382128

Text-mined citations for rs1004027979 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001370658.1(BTD):c.1036_1037dup (p.Gly347fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1004027979 ...