VCV000096590.18 - ClinVar

NM_183050.4(BCKDHB):c.508C>T (p.Arg170Cys)

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.

(6)

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/Likely 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_183050.4(BCKDHB):c.508C>T (p.Arg170Cys)

Variation ID: 96590 Accession: VCV000096590.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q14.1 6: 80168905 (GRCh38) [ NCBI UCSC ] 6: 80878622 (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	Jun 28, 2015	Jun 17, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_183050.4:c.508C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_898871.1:p.Arg170Cys	missense
NM_000056.5:c.508C>T	NP_000047.1:p.Arg170Cys	missense
NM_001318975.1:c.298C>T	NP_001305904.1:p.Arg100Cys	missense
NM_183050.3:c.508C>T
NR_134945.2:n.531C>T		non-coding transcript variant
NC_000006.12:g.80168905C>T
NC_000006.11:g.80878622C>T
NG_009775.2:g.67279C>T

... more HGVS ... less HGVS

Protein change

R170C, R100C

Other names

Canonical SPDI

NC_000006.12:80168904:C:T

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.

Links

ClinGen: CA224301 dbSNP: rs398124581 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.
BCKDHB		-	-	GRCh38 GRCh37	780	800

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.
Maple syrup urine disease	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 9, 2024	RCV000179043.20
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 21, 2022	RCV002513854.9
Maple syrup urine disease type 1A	Pathogenic (1)	criteria provided, single submitter	Jan 30, 2024	RCV004566965.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	Sep 17, 2013	RCV000790692.12

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 (Sep 17, 2013)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000231234.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BCKDHB Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Oct 21, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003601881.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (10) PubMed: 20301495‚ 22326532‚ 25381949‚ 26453840‚ 27507644‚ 29307017‚ 31980395‚ 33300147‚ 34556729‚ 35281663 Comment: The c.508C>T (p.R170C) alteration is located in exon 5 (coding exon 5) of the BCKDHB gene. This alteration results from a C to T substitution … (more) The c.508C>T (p.R170C) alteration is located in exon 5 (coding exon 5) of the BCKDHB gene. This alteration results from a C to T substitution at nucleotide position 508, causing the arginine (R) at amino acid position 170 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/251436) total alleles studied. The highest observed frequency was 0.002% (2/113724) of European (non-Finnish) alleles. This variant has been identified in the homozygous and compound heterozygous state in several individuals with maple syrup urine disease (Li, 2015; Miryounesi, 2015; Abiri, 2017; Li, 2018; Fang, 2021; Martín-Rivada, 2022). In addition, multiple different variants at this amino acid position have been detected in patients with maple syrup urine disease including p.R170H (c.509G>A), p.R170G (c.508C>G), and p.R170P (c.509G>C)(Strauss, 2020; O'Reilly, 2021; Wang, 2012; ClinVar database). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jan 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Maple syrup urine disease type 1A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004215938.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Mar 23, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Maple syrup urine disease type 1A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000798762.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Publications: PubMed (4) PubMed: 25381949‚ 26453840‚ 27507644‚ 27682710
Likely pathogenic (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Maple syrup urine disease type 1A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002033148.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (Jan 09, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Maple syrup urine disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001591737.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 25381949‚ 26453840‚ 27682710‚ 29307017‚ 22326532 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the BCKDHB protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the BCKDHB protein (p.Arg170Cys). This variant is present in population databases (rs398124581, gnomAD 0.002%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 25381949, 26453840, 27682710, 29307017). 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: 96590). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg170 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been observed in individuals with BCKDHB-related conditions (PMID: 22326532; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

The c.508C>T (p.R170C) alteration is located in exon 5 (coding exon 5) of the BCKDHB gene. This alteration results from a C to T substitution at nucleotide position 508, causing the arginine (R) at amino acid position 170 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/251436) total alleles studied. The highest observed frequency was 0.002% (2/113724) of European (non-Finnish) alleles. This variant has been identified in the homozygous and compound heterozygous state in several individuals with maple syrup urine disease (Li, 2015; Miryounesi, 2015; Abiri, 2017; Li, 2018; Fang, 2021; Martín-Rivada, 2022). In addition, multiple different variants at this amino acid position have been detected in patients with maple syrup urine disease including p.R170H (c.509G>A), p.R170G (c.508C>G), and p.R170P (c.509G>C)(Strauss, 2020; O'Reilly, 2021; Wang, 2012; ClinVar database). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the BCKDHB protein (p.Arg170Cys). This variant is present in population databases (rs398124581, gnomAD 0.002%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 25381949, 26453840, 27682710, 29307017). 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: 96590). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg170 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been observed in individuals with BCKDHB-related conditions (PMID: 22326532; Invitae), which suggests that this may be a clinically significant amino acid residue. 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
Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region.	Martín-Rivada Á	JIMD reports	2022	PMID: 35281663
Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population.	Fang X	Scientific reports	2021	PMID: 34556729
Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland.	O'Reilly D	Journal of inherited metabolic disease	2021	PMID: 33300147
Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.	Strauss KA	Molecular genetics and metabolism	2020	PMID: 31980395
Maple Syrup Urine Disease.	Adam MP	-	2020	PMID: 20301495
Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease.	Li X	Metabolic brain disease	2018	PMID: 29307017
In silico analysis of novel mutations in maple syrup urine disease patients from Iran.	Abiri M	Metabolic brain disease	2017	PMID: 27507644
Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.	Abiri M	Journal of pediatric endocrinology & metabolism : JPEM	2016	PMID: 27682710
Eleven novel mutations of the BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease in the Chinese population: Report on eight cases.	Li X	European journal of medical genetics	2015	PMID: 26453840
A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease (MSUD).	Miryounesi M	Journal of pediatric endocrinology & metabolism : JPEM	2015	PMID: 25381949
Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD).	Wang YP	Gene	2012	PMID: 22326532
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BCKDHB	-	-	-	-
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Text-mined citations for rs398124581 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_183050.4(BCKDHB):c.508C>T (p.Arg170Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398124581 ...