ClinVar Miner

Submissions for variant NM_000017.4(ACADS):c.319C>T (p.Arg107Cys) (rs61732144)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185680 SCV000228753 pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing
GeneDx RCV000185680 SCV000238601 pathogenic not provided 2017-08-07 criteria provided, single submitter clinical testing This mutation is denoted c.319 C>T at the cDNA level or p.Arg107Cys (R107C) at the protein level. And resulting in the replacement of an Arginine codon (CGT) with a Cysteine codon (TGT) in exon 3. The R107C missense mutation in the ACADS gene has been reported previously in association with SCAD deficiency (Naito et al., 1990).
Illumina Clinical Services Laboratory,Illumina RCV000004030 SCV000376674 pathogenic Deficiency of butyryl-CoA dehydrogenase 2018-01-18 criteria provided, single submitter clinical testing The ACADS c.319C>T (p.Arg107Cys) missense variant has been reported in at least three studies in which it is found in a total of 11 patients with SCAD deficiency including in five in a homozygous state and in six in a compound heterozygous state (Naito et al. 1990; Tein et al. 2008; Waisbren et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.01943 in the Ashkenazi Jewish population of the Genome Aggregation Database with two homozygotes also reported in this population. Considering the known variable expressivity of this condition, it is not unreasonable that a homozygote might be identified in the general population for this autosomal recessive condition. Schmidt et al. (2011) and Zolkipli et al. (2011) each studied functional consequences of the p.Arg107Cys variant both in homozygous and compound heterozygous states, and demonstrated protein misfolding, reduced activity, and decreased resistance to oxidative stress in cell model systems and cultured patient cells. Based on the collective evidence, the p.Arg107Cys 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.
Invitae RCV000004030 SCV000632503 pathogenic Deficiency of butyryl-CoA dehydrogenase 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 107 of the ACADS protein (p.Arg107Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs61732144, ExAC 0.2%). This variant has been reported to be a common cause of SCAD deficiency in the Ashkenazi population although it has also been reported in several individuals from other ethnic groups (PMID: 18054510, 18523805, 18676165, 22241096). ClinVar contains an entry for this variant (Variation ID: 3826). Experimental studies have shown that this missense change leads to protein aggregration and degradation (PMID: 18523805, 21170680, 24485985). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000004030 SCV000711743 pathogenic Deficiency of butyryl-CoA dehydrogenase 2015-12-29 criteria provided, single submitter clinical testing The p.Arg107Cys variant (NM_000017.2 c.319C>T) in ACADS has been reported in at least 11 individuals with clinical features of Acyl-CoA-dehydrogenase deficiency . Three of these individuals were homozygous and 8 were compound heterozygous (N aito 1990, Tein 2008). Furthermore, this variant and has been suggested to be a founder mutation in individuals of Ashkenazi Jewish origin (Tein 2008). In vitro functional studies provide some evidence that the p.Arg107Cys variant may impac t protein function (Tein 2008, Schmidt 2011, Edhager 2014). This variant has als o been reported in ClinVar (Variation ID#3826) as pathogenic. It has been identi fied in 1.9% (184/9472) of Ashkenazi Jewish chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP 61732144). Although this variant has been seen in the general population, its frequency is low enoug h to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for Acyl-CoA-dehydrogenase def iciency in an autosomal recessive manner based upon genetic and functional evide nce. ACMG/AMP Criteria applied: PM3_Very Strong, PS3, PP5.
Fulgent Genetics,Fulgent Genetics RCV000004030 SCV000893276 pathogenic Deficiency of butyryl-CoA dehydrogenase 2018-10-31 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000004030 SCV000930208 uncertain significance Deficiency of butyryl-CoA dehydrogenase 2019-04-27 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000004030 SCV001194217 pathogenic Deficiency of butyryl-CoA dehydrogenase 2019-11-12 criteria provided, single submitter clinical testing NM_000017.2(ACADS):c.319C>T(R107C) is classified as pathogenic in the context of short-chain acyl-CoA dehydrogenase deficiency. Sources cited for classification include the following: PMID 18523805, 1692038, 18054510, 22424739, 24485985 and 21170680. Classification of NM_000017.2(ACADS):c.319C>T(R107C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000004030 SCV000024196 pathogenic Deficiency of butyryl-CoA dehydrogenase 2008-02-01 no assertion criteria provided literature only
GeneReviews RCV000004030 SCV000188412 pathogenic Deficiency of butyryl-CoA dehydrogenase 2014-08-07 no assertion criteria provided literature only
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000004030 SCV000223916 pathogenic Deficiency of butyryl-CoA dehydrogenase 2015-02-02 no assertion criteria provided clinical testing
Myriad Women's Health, Inc. RCV000004030 SCV000485196 pathogenic Deficiency of butyryl-CoA dehydrogenase 2016-03-11 no assertion criteria provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000004030 SCV001142437 pathogenic Deficiency of butyryl-CoA dehydrogenase 2020-01-06 no assertion criteria provided curation NM_000017.2:c.319C>T in the ACADS gene has an allele frequency of 0.019 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that p.Arg107Cys give rise to inactive misfolded protein species, eliciting a mild toxic response manifested though a decreased proliferation rate and oxidative stress (PMID: 21170680). This variant has been reported as a founder mutation in individuals of Ashkenazi Jewish origin (PMID: 18054510).Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS4; PS3; PP3; PP4; BS1.

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