VCV000009202.50 - ClinVar

NM_001609.4(ACADSB):c.443C>T (p.Thr148Ile)

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.

(11)

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(4); Likely pathogenic(4); 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_001609.4(ACADSB):c.443C>T (p.Thr148Ile)

Variation ID: 9202 Accession: VCV000009202.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q26.13 10: 123040605 (GRCh38) [ NCBI UCSC ] 10: 124800121 (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	Nov 17, 2024	Oct 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001609.4:c.443C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001600.1:p.Thr148Ile	missense
NM_001330174.3:c.137C>T	NP_001317103.1:p.Thr46Ile	missense
NC_000010.11:g.123040605C>T
NC_000010.10:g.124800121C>T
NG_008003.1:g.36693C>T
LRG_451:g.36693C>T
LRG_451t1:c.443C>T	LRG_451p1:p.Thr148Ile

... more HGVS ... less HGVS

Protein change

T148I, T46I

Other names

Canonical SPDI

NC_000010.11:123040604: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.

0.00060 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00050

1000 Genomes Project 0.00060

The Genome Aggregation Database (gnomAD) 0.00060

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069

Exome Aggregation Consortium (ExAC) 0.00079

The Genome Aggregation Database (gnomAD), exomes 0.00083

1000 Genomes Project 30x 0.00094

Links

ClinGen: CA120176 OMIM: 600301.0004 dbSNP: rs58639322 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.
ACADSB		-	-	GRCh38 GRCh37	306	365

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.
Deficiency of 2-methylbutyryl-CoA dehydrogenase	Conflicting interpretations of pathogenicity (8)	criteria provided, conflicting classifications	Oct 9, 2024	RCV000009780.29
not provided	Likely pathogenic (2)	criteria provided, single submitter	Jan 1, 2023	RCV000389934.29
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 13, 2021	RCV002512950.3

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.
Likely pathogenic (Jun 26, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Deficiency of 2-methylbutyryl-CoA dehydrogenase Affected status: unknown Allele origin: inherited	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001761004.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021	Clinical Features: Autism (present) , Intellectual disability (present) , Failure to thrive (present) , Delayed speech and language development (present) , eosinophilic infiltration of the esophagus (present) Secondary finding: no
Uncertain significance (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of 2-methylbutyryl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004810376.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely pathogenic (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of 2-methylbutyryl-CoA dehydrogenase (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001251416.2 First in ClinVar: May 31, 2020 Last updated: Nov 17, 2024	Clinical Features: Hypotonia (present) , Intellectual disability (present) , Motor delay (present) , Global developmental delay (present) Sex: male
Pathogenic (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Deficiency of 2-methylbutyryl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915461.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (3) PubMed: 20547083‚ 15615815‚ 17945527 Comment: The ACADSB c.443C>T (p.Thr148Ile) missense variant has been reported in at least three studies in which it is found in a total of six patients … (more) The ACADSB c.443C>T (p.Thr148Ile) missense variant has been reported in at least three studies in which it is found in a total of six patients with acyl-CoA dehydrogenase, short/branched chain deficiency, including in three, of whom two are siblings, who carried the variant in a homozygous state, and three, of whom two are siblings, who carried the variant in a compound heterozygous state (Korman et al. 2005; Sass et al. 2008; Alfardan et al. 2010). The p.Thr148Ile variant was not detected in 92 control chromosomes and is reported at a frequency of 0.0023 in the South Asian population of the Exome Aggregation Consortium. In vitro expression in E. coli found that the p.Thr148Ile variant protein had almost undetectable activity compared to wild type (Alfardan et al. 2010). It should be noted that some individuals with this disorder may remain asymptomatic throughout life. Based on the evidence, the p.Thr148Ile variant is classified as pathogenic for acyl-CoA dehydrogenase, short/branched chain deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Nov 26, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Deficiency of 2-methylbutyryl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002766172.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 20547083‚ 15615815‚ 30730842‚ 17945527 Comment: Variant summary: ACADSB c.443C>T (p.Thr148Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. … (more) Variant summary: ACADSB c.443C>T (p.Thr148Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251424 control chromosomes (gnomAD). c.443C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Deficiency Of 2-Methylbutyryl Dehydrogenase (e.g. Korman_2005, Sass_2008, Porta_2019). These data indicate that the variant is very likely to be associated with disease. When the variant was expressed in E. coli, the variant had minimal protein yield and 2.8% normal activity (Alfardan_2010). Seven ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, one as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of 2-methylbutyryl-CoA dehydrogenase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001527950.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 18, 2023
Pathogenic (Jan 10, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of 2-methylbutyryl-CoA dehydrogenase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000645153.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 15615815‚ 17945527‚ 20547083‚ 30730842 Comment: This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 148 of the ACADSB protein (p.Thr148Ile). … (more) This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 148 of the ACADSB protein (p.Thr148Ile). This variant is present in population databases (rs58639322, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with SBCAD deficiency (PMID: 15615815, 17945527, 20547083, 30730842). ClinVar contains an entry for this variant (Variation ID: 9202). 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 not expected to disrupt ACADSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADSB function (PMID: 20547083). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 13, 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: SCV003741195.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 15615815‚ 17945527‚ 20547083‚ 30730842 Comment: The c.443C>T (p.T148I) alteration is located in exon 4 (coding exon 4) of the ACADSB gene. This alteration results from a C to T substitution … (more) The c.443C>T (p.T148I) alteration is located in exon 4 (coding exon 4) of the ACADSB gene. This alteration results from a C to T substitution at nucleotide position 443, causing the threonine (T) at amino acid position 148 to be replaced by an isoleucine (I). This variant has been reported in individuals with biochemical evidence of 2-methylbutyrylglycinuria in both the homozygous and compound heterozygous state; however, most were reported as clinically asymptomatic (Korman, 2005; Sass, 2008; Alfardan, 2010; Porta, 2019). One individual presented with a history of metabolic acidosis and coma during illness (Porta, 2019). In E. coli with this variant, enzyme activity was reduced to 2.8% of wild type activity levels (Alfardan, 2010). The in silico prediction for the p.T148I alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Likely pathogenic (Jan 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247458.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: ACADSB: PM3:Strong, PM2, PP4:Moderate, PS3:Supporting Number of individuals with the variant: 2
Pathogenic (Jan 01, 2008)	no assertion criteria provided Method: literature only	2-@METHYLBUTYRYL-CoA DEHYDROGENASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030001.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 14, 2020	Publications: PubMed (2) PubMed: 17945527‚ 20547083 Comment on evidence: In 2 brothers, born of a consanguineous Arab couple from Lebanon, with 2-methylbutyryl-CoA dehydrogenase deficiency (610006), Sass et al. (2008) identified compound heterozygosity for mutations … (more) In 2 brothers, born of a consanguineous Arab couple from Lebanon, with 2-methylbutyryl-CoA dehydrogenase deficiency (610006), Sass et al. (2008) identified compound heterozygosity for mutations in the ACADSB gene: a 443C-T transition in exon 4, resulting in a thr148-to-ile (T148I) substitution, and a 1159G-A transition in exon 10, resulting in a glu387-to-lys (E387K; 600301.0005) substitution. One brother was diagnosed by newborn screening, and the other was diagnosed at age 3 years after his brother's diagnosis. Neither patient showed any clinical abnormalities, and both had normal development, but were lost to follow-up when the proband was 10 months old. The authors also identified homozygosity for the T148I mutation in 2 sibs from a consanguineous Turkish family. Both boys had normal development at age 6 and 7 years, respectively. In vitro studies of patient fibroblasts confirmed an impairment in isoleucine degradation. In a child of European ancestry who was identified by newborn screening to have 2-methybutyryl-CoA dehydrogenase deficiency, Alfardan et al. (2010) identified compound heterozygosity for the T148I and E387K mutations. Alfardan et al. (2010) introduced the T148I mutation into an SBCAD expression vector and expressed it in E. coli. SBCAD protein was not detectable by Western blot analysis, and SBCAD enzyme activity was absent. Molecular modeling showed that the T148 residue resides in a hydrophilic pocket, where an Ile substitution might be disruptive. (less)
Uncertain significance (Apr 08, 2016)	Flagged submission flagged submission (EGL Classification Definitions 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000341243.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADSB Number of individuals with the variant: 1 Sex: mixed
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Comment:

The ACADSB c.443C>T (p.Thr148Ile) missense variant has been reported in at least three studies in which it is found in a total of six patients with acyl-CoA dehydrogenase, short/branched chain deficiency, including in three, of whom two are siblings, who carried the variant in a homozygous state, and three, of whom two are siblings, who carried the variant in a compound heterozygous state (Korman et al. 2005; Sass et al. 2008; Alfardan et al. 2010). The p.Thr148Ile variant was not detected in 92 control chromosomes and is reported at a frequency of 0.0023 in the South Asian population of the Exome Aggregation Consortium. In vitro expression in E. coli found that the p.Thr148Ile variant protein had almost undetectable activity compared to wild type (Alfardan et al. 2010). It should be noted that some individuals with this disorder may remain asymptomatic throughout life. Based on the evidence, the p.Thr148Ile variant is classified as pathogenic for acyl-CoA dehydrogenase, short/branched chain deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Variant summary: ACADSB c.443C>T (p.Thr148Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251424 control chromosomes (gnomAD). c.443C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Deficiency Of 2-Methylbutyryl Dehydrogenase (e.g. Korman_2005, Sass_2008, Porta_2019). These data indicate that the variant is very likely to be associated with disease. When the variant was expressed in E. coli, the variant had minimal protein yield and 2.8% normal activity (Alfardan_2010). Seven ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, one as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 148 of the ACADSB protein (p.Thr148Ile). This variant is present in population databases (rs58639322, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with SBCAD deficiency (PMID: 15615815, 17945527, 20547083, 30730842). ClinVar contains an entry for this variant (Variation ID: 9202). 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 not expected to disrupt ACADSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADSB function (PMID: 20547083). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.443C>T (p.T148I) alteration is located in exon 4 (coding exon 4) of the ACADSB gene. This alteration results from a C to T substitution at nucleotide position 443, causing the threonine (T) at amino acid position 148 to be replaced by an isoleucine (I). This variant has been reported in individuals with biochemical evidence of 2-methylbutyrylglycinuria in both the homozygous and compound heterozygous state; however, most were reported as clinically asymptomatic (Korman, 2005; Sass, 2008; Alfardan, 2010; Porta, 2019). One individual presented with a history of metabolic acidosis and coma during illness (Porta, 2019). In E. coli with this variant, enzyme activity was reduced to 2.8% of wild type activity levels (Alfardan, 2010). The in silico prediction for the p.T148I alteration is inconclusive. Based on the available evidence, this alteration is classified as likely 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, biochemical, and molecular spectrum of short/branched-chain acyl-CoA dehydrogenase deficiency: two new cases and review of literature.	Porta F	Journal of pediatric endocrinology & metabolism : JPEM	2019	PMID: 30730842
Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening.	Alfardan J	Molecular genetics and metabolism	2010	PMID: 20547083
2-Methylbutyryl-coenzyme A dehydrogenase deficiency: functional and molecular studies on a defect in isoleucine catabolism.	Sass JO	Molecular genetics and metabolism	2008	PMID: 17945527
2-ethylhydracrylic aciduria in short/branched-chain acyl-CoA dehydrogenase deficiency: application to diagnosis and implications for the R-pathway of isoleucine oxidation.	Korman SH	Clinical chemistry	2005	PMID: 15615815
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADSB	-	-	-	-

Text-mined citations for rs58639322 ...

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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_001609.4(ACADSB):c.443C>T (p.Thr148Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs58639322 ...