ClinVar Miner

Submissions for variant NM_000017.4(ACADS):c.1058C>T (p.Ser353Leu)

gnomAD frequency: 0.00022  dbSNP: rs28941773
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185693 SCV000238614 pathogenic not provided 2020-10-16 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Corydon et al., 2001; Pedersen et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11134486, 16926354, 28532786, 18523805, 28263315, 21500142, 31980526)
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000004040 SCV000746500 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2017-12-03 criteria provided, single submitter clinical testing
Invitae RCV000004040 SCV000756743 pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-08-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000185693 SCV000883331 likely pathogenic not provided 2017-12-12 criteria provided, single submitter clinical testing The ACADS p.Ser353Leu variant (rs28941773) has been reported in two individuals with a diagnosis of short-chain acyl-CoA dehydrogenase (SCAD) deficiency who also had a common risk factor variant (Corydon 2001 and Dessein 2017). Furthermore, functional studies show that the ACADS protein harboring the p.Ser353Leu variant does not have detectable enzymatic activity compared to wild type when expressed in bacteria (Corydon 2001). The p.Ser353Leu variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.044% in the non-Finnish European population (identified in 54 out of 123,600 chromosomes), which is consistent with a recessive carrier frequency. This variant is also present in the ClinVar database (Variant ID: 3836). Therefore, based on the available evidence, the p.Ser353Leu variant is classified as likely pathogenic.
Illumina Laboratory Services,Illumina RCV000004040 SCV000914566 pathogenic Deficiency of butyryl-CoA dehydrogenase 2018-10-19 criteria provided, single submitter clinical testing The ACADS c.1058C>T (p.Ser353Leu) missense variant has been reported in two studies in which it is identified in at least seven probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency, all in a compound heterozygous state with the common susceptibility allele, c.625C>T (Corydon et al. 2001; Van Maldegem et al. 2010). The p.Ser353Leu variant was reported in 5 of 959 controls in a heterozygous state and in one control along with the c.625C>T variant where zygosity is not confirmed (Corydon et al. 2001; Van Maldegem et al. 2011). The p.Ser353Leu is also reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functionally, SCAD enzyme activity was significantly reduced in E. coli expressing the p.Ser329Leu variant protein compared to wild type (Corydon et al. 2001). Of note, individuals with SCAD deficiency show variable expressivity of this condition, even among affected family members, and some individuals with a molecular diagnosis are asymptomatic into adulthood. Based on the collective evidence, the p.Ser353Leu variant is classified as pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen RCV000185693 SCV001148848 likely pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000004040 SCV002033256 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-11-07 criteria provided, single submitter clinical testing
OMIM RCV000004040 SCV000024206 pathogenic Deficiency of butyryl-CoA dehydrogenase 2001-01-01 no assertion criteria provided literature only
Counsyl RCV000004040 SCV000678148 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2018-06-21 no assertion criteria provided clinical testing

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