ClinVar Miner

Submissions for variant NM_000017.4(ACADS):c.1058C>T (p.Ser353Leu) (rs28941773)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185693 SCV000238614 likely pathogenic not provided 2017-01-12 criteria provided, single submitter clinical testing The S353L missense variant in the ACADS gene has been reported previously as S329L in a patient with 10% of control short chain acyl-CoA dehydrogenase (SCAD) enzyme activity in fibroblasts who harbored the G209S reportable variant on the opposite ACADS allele (Corydon et al., 2001). Expression of S353L in E. coli found that is associated with undetectable SCAD enzyme activity compared to wild-type (Corydon et al., 2001). Therefore, we interpret S353L to be a likely pathogenic variant.
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 uncertain significance Deficiency of butyryl-CoA dehydrogenase 2018-04-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 353 of the ACADS protein (p.Ser353Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs28941773, ExAC 0.02%). This variant has been reported in individuals affected with short-chain acyl-CoA dehydrogenase deficiency (SCADD) in combination with the common benign variants c.625G>A or c.511C>T (PMID: 11134486, 18523805). ClinVar contains an entry for this variant (Variation ID: 3836). Experimental studies have shown that this missense change causes defects on ACADS protein assembly and abrogates enzymatic activity in vitro (PMID: 11134486, 18523805). 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.
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 Clinical Services Laboratory,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 Praxis fuer Humangenetik Tuebingen RCV000185693 SCV001148848 likely pathogenic not provided 2016-06-01 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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