VCV000971110.11 - ClinVar

NM_001370658.1(BTD):c.1496A>G (p.Tyr499Cys)

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.

Uncertain significance

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.1496A>G (p.Tyr499Cys)

Variation ID: 971110 Accession: VCV000971110.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.1 3: 15645412 (GRCh38) [ NCBI UCSC ] 3: 15686919 (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	Jul 16, 2020	May 1, 2024	Sep 27, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001370658.1:c.1496A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001357587.1:p.Tyr499Cys	missense
NM_000060.2:c.1556A>G
NM_000060.4:c.1556A>G	NP_000051.1:p.Tyr519Cys	missense
NM_001281723.4:c.1496A>G	NP_001268652.2:p.Tyr499Cys	missense
NM_001281724.3:c.1496A>G	NP_001268653.2:p.Tyr499Cys	missense
NM_001281725.3:c.1496A>G	NP_001268654.1:p.Tyr499Cys	missense
NM_001281726.2:c.*3274A>G
NM_001323582.2:c.1496A>G	NP_001310511.1:p.Tyr499Cys	missense
NM_001370752.1:c.1015+481A>G		intron variant
NM_001370753.1:c.399+3355A>G		intron variant
NM_001407364.1:c.1496A>G	NP_001394293.1:p.Tyr499Cys	missense
NM_001407365.1:c.1496A>G	NP_001394294.1:p.Tyr499Cys	missense
NM_001407366.1:c.1496A>G	NP_001394295.1:p.Tyr499Cys	missense
NM_001407367.1:c.1496A>G	NP_001394296.1:p.Tyr499Cys	missense
NM_001407368.1:c.1496A>G	NP_001394297.1:p.Tyr499Cys	missense
NM_001407369.1:c.1496A>G	NP_001394298.1:p.Tyr499Cys	missense
NM_001407370.1:c.1496A>G	NP_001394299.1:p.Tyr499Cys	missense
NM_001407371.1:c.1496A>G	NP_001394300.1:p.Tyr499Cys	missense
NM_001407372.1:c.1496A>G	NP_001394301.1:p.Tyr499Cys	missense
NM_001407373.1:c.1496A>G	NP_001394302.1:p.Tyr499Cys	missense
NM_001407374.1:c.1496A>G	NP_001394303.1:p.Tyr499Cys	missense
NM_001407375.1:c.1496A>G	NP_001394304.1:p.Tyr499Cys	missense
NM_001407376.1:c.1496A>G	NP_001394305.1:p.Tyr499Cys	missense
NM_001407377.1:c.1496A>G	NP_001394306.1:p.Tyr499Cys	missense
NM_001407378.1:c.1496A>G	NP_001394307.1:p.Tyr499Cys	missense
NM_001407379.1:c.1015+481A>G		intron variant
NM_001407380.1:c.399+3355A>G		intron variant
NM_001407398.1:c.399+3355A>G		intron variant
NM_001407399.1:c.399+3355A>G		intron variant
NM_001407400.1:c.399+3355A>G		intron variant
NM_001407401.1:c.399+3355A>G		intron variant
NC_000003.12:g.15645412A>G
NC_000003.11:g.15686919A>G
NG_008019.2:g.49061A>G
NG_008019.3:g.49062A>G

... more HGVS ... less HGVS

Protein change

Y499C, Y519C

Other names

Canonical SPDI

NC_000003.12:15645411:A:G

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.

0.00020 (G)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00001

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

dbSNP: rs199859507 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	669	755

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	Uncertain significance (2)	criteria provided, single submitter	Aug 27, 2021	RCV001246806.9
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Sep 27, 2021	RCV002568667.2

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 (Aug 27, 2021)	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: SCV001420191.3 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Comment: This sequence change replaces tyrosine with cysteine at codon 519 of the BTD protein (p.Tyr519Cys). The tyrosine residue is moderately conserved and there is a … (more) This sequence change replaces tyrosine with cysteine at codon 519 of the BTD protein (p.Tyr519Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs199859507, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with BTD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 27, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003746299.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.1556A>G (p.Y519C) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a A to G substitution … (more) The c.1556A>G (p.Y519C) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a A to G substitution at nucleotide position 1556, causing the tyrosine (Y) at amino acid position 519 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 27, 2020)	no assertion criteria provided Method: clinical testing	Biotinidase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002081578.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change replaces tyrosine with cysteine at codon 519 of the BTD protein (p.Tyr519Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs199859507, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with BTD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The c.1556A>G (p.Y519C) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a A to G substitution at nucleotide position 1556, causing the tyrosine (Y) at amino acid position 519 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs199859507 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001370658.1(BTD):c.1496A>G (p.Tyr499Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199859507 ...