ClinVar Miner

Submissions for variant NM_000017.4(ACADS):c.529T>C (p.Trp177Arg)

gnomAD frequency: 0.00202  dbSNP: rs57443665
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000004032 SCV000220594 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2014-08-22 criteria provided, single submitter literature only
GeneDx RCV000185684 SCV000238605 pathogenic not provided 2022-04-28 criteria provided, single submitter clinical testing Reported previously in association with short chain acyl-CoA dehydrogenase (SCAD) deficiency using alternative nomenclature (Gregersen et al., 1998); Functional analysis found that this variant is associated with significantly reduced enzyme activity compared to wild-type (Gregersen et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18523805, 12736383, 28263315, 16546179, 18676165, 22241096, 23798014, 22424739, 9499414, 31589614, 31813752, 32778825, 27535533)
Fulgent Genetics,Fulgent Genetics RCV000004032 SCV000611158 pathogenic Deficiency of butyryl-CoA dehydrogenase 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000004032 SCV000632509 pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-12-02 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 177 of the ACADS protein (p.Trp177Arg). This variant is present in population databases (rs57443665, gnomAD 0.7%). This missense change has been observed in individuals with SCAD deficiency (PMID: 9499414, 12736383, 18676165, 22241096). ClinVar contains an entry for this variant (Variation ID: 3828). 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: 9499414, 18523805). For these reasons, this variant has been classified as Pathogenic.
Eurofins NTD LLC (GA) RCV000185684 SCV000703978 pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000004032 SCV002033278 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-11-07 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251868 SCV002524031 likely pathogenic See cases 2019-06-18 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PM2, PM3, PP3
New York Genome Center RCV000004032 SCV002548619 pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-07-23 criteria provided, single submitter clinical testing The homozygous c.529T>C (p.Trp177Arg) variant identified in the ACADS gene substitutes a well conserved Tryptophan for Arginine at amino acid177/413 (exon 5/10). This variant is found with appreciable frequency in gnomAD (279 heterozygotes, 3 homozygotes; allele frequency:1.83e-3). In silico algorithms predict it to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.957) to the function of the canonical transcript. This variant is reported as LikelyPathogenic/Pathogenic in ClinVar (VarID:3828) and has been reported in many individuals in the literature with biochemical findings consistent with SCADD [PMID:9499414, 18523805, 23798014, others]. Functional studies suggest it significantly impairs enzyme activity [PMID:9499414]. The homozygous c.529T>C(p.Trp177Arg) variant identified in the ACADS gene is reported as Pathogenic.
OMIM RCV000004032 SCV000024198 pathogenic Deficiency of butyryl-CoA dehydrogenase 1998-04-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000004032 SCV001142438 pathogenic Deficiency of butyryl-CoA dehydrogenase 2020-01-06 no assertion criteria provided curation NM_000017.2:c.529T>C in the ACADS gene has an allele frequency of 0.007 in Africa subpopulation in the gnomAD database. Functional studies demonstrate that c.529T>C has affected aggregation and abolishes enzymatic activity of the encoded protein (PMID: 9499414; 18523805). It was detected in multiple individuals with autosomal recessive Deficiency of butyryl-CoA dehydrogenase, two homozygous c.529T>C (p.Trp177Arg), compound heterozygous with c.988C>T (p.Arg330Cys) (PMID: 22241096; 18676165; 12736383). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4.
PerkinElmer Genomics RCV000004032 SCV002021051 pathogenic Deficiency of butyryl-CoA dehydrogenase 2021-10-29 no assertion criteria provided clinical testing

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