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

gnomAD frequency: 0.00060  dbSNP: rs58639322

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000009780	SCV000645153	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2024-01-10	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000009780	SCV000915461	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2017-04-28	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000389934	SCV001247458	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	ACADSB: PM3:Strong, PM2, PP4:Moderate, PS3:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009780	SCV001251416	uncertain significance	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2019-10-14	criteria provided, single submitter	clinical testing	The variant was confirmed as compound heterozygous with a likely pathogenic variant (NM_001609.3: c.1228+2T>C).
Baylor Genetics	RCV000009780	SCV001527950	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase		criteria provided, single submitter	clinical testing
New York Genome Center	RCV000009780	SCV001761004	likely pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2020-06-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000009780	SCV002766172	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2022-11-26	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002512950	SCV003741195	likely pathogenic	Inborn genetic diseases	2021-01-13	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000009780	SCV004810376	uncertain significance	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000009780	SCV000030001	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2008-01-01	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000389934	SCV000341243	uncertain significance	not provided	2016-04-08	flagged submission	clinical testing