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

gnomAD frequency: 0.00202  dbSNP: rs57443665

Total submissions: 19

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	2022-11-21	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 supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18523805, 12736383, 28263315, 16546179, 18676165, 22241096, 23798014, 22424739, 9499414, 31589614, 31813752, 32778825)
Fulgent Genetics, Fulgent Genetics	RCV000004032	SCV000611158	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-03-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004032	SCV000632509	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-01-29	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%), and has an allele count higher than expected for a pathogenic variant. 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 with a positive predictive value of 95%. 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
Revvity Omics, Revvity	RCV000004032	SCV002021051	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-10-15	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
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.
MGZ Medical Genetics Center	RCV000004032	SCV002580354	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512732	SCV003584295	pathogenic	Inborn genetic diseases	2021-07-09	criteria provided, single submitter	clinical testing	The c.529T>C (p.W177R) alteration is located in exon 5 (coding exon 5) of the ACADS gene. This alteration results from a T to C substitution at nucleotide position 529, causing the tryptophan (W) at amino acid position 177 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the ACADS c.529T>C alteration was observed in 0.06% (174/282582) of total alleles studied, with a frequency of 0.67% (168/24930) in the African subpopulation. This alteration has been reported as homozygous and compound heterozygous in multiple individuals with biochemical diagnoses of short-chain acyl-CoA dehydrogenase deficiency (Waisbren, 2008; Pedersen, 2008; Gregersen, 1998; Koeberl, 2003; Pena, 2012; Maguolo, 2020). This amino acid position is highly conserved in available vertebrate species. In a ferricenium ion-based enzyme activity assay, this alteration had no detectable activity above background (Gregersen, 1998) The p.W177R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000004032	SCV003807320	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-09-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000185684	SCV004223890	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004032	SCV004847349	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-10-02	criteria provided, single submitter	clinical testing	The p.Trp177Arg variant in ACADS has been reported in the homozygous state in at least 7 individuals and in the compound heterozygous state in 11 individuals with short chain acyl-CoA dehydrogenase deficiency (SCADD) that was detected from biochemical evaluations; however, many of these individuals were asymptomatic at the time of study (Gregersen 1998 PMID: 9499414, Koeberl 2003 PMID: 12736383, Waisbren 2008 PMID: 18676165, Pena 2012 PMID: 22241096, Maguolo 2020 PMID: 32793418, Sadat 2020 PMID: 31813752). It has also been reported by other clinical laboratories in ClinVar (Variation ID 3828) and has been identified in 0.6% (261/41434) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), including 3 homozygotes, which is consistent with the frequency and manifestation of SCADD in the generation population. In vitro functional studies provide evidence that this variant reduces enzyme activity (Gregersen 1998 PMID: 9499414) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive SCADD. ACMG/AMP Criteria applied: PM3_Strong, PP3, PS3_Supporting, PP4.
Baylor Genetics	RCV000004032	SCV005049838	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-12-10	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000004032	SCV005200816	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-05-22	criteria provided, single submitter	clinical testing	PS3, PM3_Very Strong
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004032	SCV005204460	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-06-11	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.529T>C (p.Trp177Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of 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 0.00045 in 251254 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADS causing Deficiency Of Butyryl-CoA Dehydrogenase, allowing no conclusion about variant significance. c.529T>C has been reported in the literature in multiple individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (example: Gregerson_1998, Koeberl_2003, Waisbren_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Gregerson_1998). The following publications have been ascertained in the context of this evaluation (PMID: 12736383, 18676165, 9499414). ClinVar contains an entry for this variant (Variation ID: 3828). Based on the evidence outlined above, the variant was classified 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.
PreventionGenetics, part of Exact Sciences	RCV004748494	SCV005355951	pathogenic	ACADS-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The ACADS c.529T>C variant is predicted to result in the amino acid substitution p.Trp177Arg. This variant, which has also been described as W153R, has been reported in the homozygous or compound heterozygous state in multiple patients with autosomal recessive short chain acyl-CoA dehydrogenase deficiency, although it should be noted that not all reported patients were clinically symptomatic (Gregersen et al. 1998. PubMedID: 9499414; Koeberl et al. 2003. PubMedID: 12736383; Pedersen et al. 2008. PubMed ID: 18523805; Waisbren et al. 2008. PubMed ID: 18676165; Waisbren et al. 2013. PubMed ID: 23798014). In experimental studies, the p.Trp177Arg substitution lead to near complete loss of enzyme activity, disrupted tetramer formation, and increased aggregation tendency (Gregersen et al. 1998. PubMedID: 9499414; Pedersen et al. 2008. PubMed ID: 18523805). In summary, we classify this variant as pathogenic.