Submissions for variant NM_000017.4(ACADS):c.164C>T (p.Pro55Leu)

gnomAD frequency: 0.00001  dbSNP: rs147442301

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000023585	SCV000793186	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2017-07-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000023585	SCV000914564	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2018-08-14	criteria provided, single submitter	clinical testing	The ACADS c.164C>T (p.Pro55Leu) missense variant has been reported in four studies in which it is found in a total of six individuals with SCAD deficiency, including in one with the variant in a homozygous state and in five in a compound heterozygous state. All individuals carrying the variant were diagnosed with SCAD deficiency through newborn screening and were clinically asymptomatic, even during follow-up in childhood (Jethva and Ficicioqlu 2008; Shirao et al. 2010; An et al. 2016; Kim et al. 2016). In addition, Huang et al. (2016) reported the p.Pro55Leu variant in approximately 20% of 17 clinically asymptomatic Chinese children who were identified through newborn screening as having SCAD deficiency. Control data are unavailable for this variant, which is reported at a frequency of 0.00092 in the East Asian population of the Exome Aggregation Consortium. Shirao et al. (2010) performed in vitro testing of the variant and found that HEK293 cells that were transfected with the variant protein had 6.67% enzymatic activity compared to wild type. When the variant was co-transfected with wild type protein, 60-70% of normal enzymatic activity was observed. Based on the collective evidence, the p.Pro55Leu variant is classified as pathogenic for SCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genome-Nilou Lab	RCV000023585	SCV002033277	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000023585	SCV002243243	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-04-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 55 of the ACADS protein (p.Pro55Leu). This variant is present in population databases (rs147442301, gnomAD 0.05%). This missense change has been observed in individuals with short chain acyl-CoA dehydrogenase deficiency (PMID: 18951053, 20376488, 27938594, 28018444). ClinVar contains an entry for this variant (Variation ID: 30611). 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 expected to disrupt ACADS protein function. Experimental studies have shown that this missense change affects ACADS function (PMID: 20376488). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000023585	SCV004020926	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-06-09	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.164C>T (p.Pro55Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251496 control chromosomes. c.164C>T has been reported in the literature as a compound heterozygous genotype in settings of biochemically confirmed diagnosis/newborn screen for Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (example, Shirao_2010, An_2016, Huang_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Shirao_2010). The most pronounced variant effect results in <10% of normal SCAD enzymatic activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 28018444, 35193651, 20376488). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000023585	SCV000044876	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2010-06-01	no assertion criteria provided	literature only