rs61732144
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 18P and 2B. PS1PM1PM5PP2PP3PP5_Very_StrongBP4BS2_Supporting
The NM_000017.4(ACADS):c.319C>T(p.Arg107Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,597,502 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000017.4 missense
Scores
Clinical Significance
Conservation
Publications
- short chain acyl-CoA dehydrogenase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ACADS | ENST00000242592.9 | c.319C>T | p.Arg107Cys | missense_variant | Exon 3 of 10 | 1 | NM_000017.4 | ENSP00000242592.4 | ||
| ACADS | ENST00000411593.2 | c.319C>T | p.Arg107Cys | missense_variant | Exon 3 of 10 | 2 | ENSP00000401045.2 | |||
| ACADS | ENST00000539690.1 | n.431C>T | non_coding_transcript_exon_variant | Exon 3 of 3 | 2 | |||||
| ENSG00000255946 | ENST00000724268.1 | n.305-6806G>A | intron_variant | Intron 1 of 1 |
Frequencies
GnomAD3 genomes 0.000532 AC: 81AN: 152246Hom.: 2 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000970 AC: 213AN: 219678 AF XY: 0.000901 show subpopulations
GnomAD4 exome AF: 0.000499 AC: 721AN: 1445256Hom.: 7 Cov.: 31 AF XY: 0.000506 AC XY: 363AN XY: 717420 show subpopulations
Age Distribution
GnomAD4 genome 0.000532 AC: 81AN: 152246Hom.: 2 Cov.: 33 AF XY: 0.000605 AC XY: 45AN XY: 74386 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Deficiency of butyryl-CoA dehydrogenase Pathogenic:13Other:1
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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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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. -
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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. -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 107 of the ACADS protein (p.Arg107Cys). This variant is present in population databases (rs61732144, gnomAD 1.9%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with SCAD deficiency (PMID: 18054510, 18523805, 18676165, 22241096). It is commonly reported in individuals of Ashkenazi ancestry (PMID: 18054510, 18523805, 18676165, 22241096). ClinVar contains an entry for this variant (Variation ID: 3826). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACADS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACADS function (PMID: 18523805, 21170680, 24485985). For these reasons, this variant has been classified as Pathogenic. -
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. -
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Variant summary: ACADS c.319C>T (p.Arg107Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR013786) 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 0.00097 in 219678 control chromosomes, predominantly at a frequency of 0.019 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 2 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, it has been reported in the literature that the high allele frequency in the Ashkenazi Jewish subpopulation suggests the variant may be a founder mutation in this subpopulation (e.g. Tein_2008). c.319C>T has been reported in the literature in mulitple homozygous and compound heterozygous individuals, including at least 10 patients of Ashkenazi Jewish descent, affected with Deficiency Of Butyryl-CoA Dehydrogenase (e.g., Tein_2008, Pedersen_2008). The variant was also identified in several asymptomatic compound heterozygous parents with the same genotypes as their affected children (e.g., Tein_2008). These data indicate that the variant is very likely to be associated with disease, although the variant may have reduced penetrance and results in significant clinical heterogeneity. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant leads to a severe protein folding defect, the inability to produce homotetramers, and increased protein aggregation and chaperone complex formation (e.g., Tein_2008, Schmidt_2011, Pedersen_2008). These studies found that the variant results in approximately 10% of normal enzymatic activity (e.g., Tein_2008, Schmidt_2011). Additional experimental studies also suggest an oxidative imbalance may be necessary prior to the manifestation of clinical symptoms (e.g., Zolkipli_2011). The following publications have been ascertained in the context of this evaluation (PMID: 18523805, 21170680, 18054510, 21483766). Fourteen submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Thirteen submitters classified the variant as pathogenic, while one submitter classified the variant as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:3
PS3, PS4_moderate, PM2, PP3, PP4, PP5 -
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Expression studies found that R107C is associated with no residual short chain acyl-CoA dehydrogenase activity (Schmidt et al. 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25333069, 22975760, 18054510, 21483766, 31737040, 21170680, 24485985, 1692038, 28516284, 29555771, 20429031, 18676165, 18523805, 18500942, 29431110, 30487145, 30609409, 22241096, 31620161, 31813752, 31980526) -
Inborn genetic diseases Pathogenic:1
The c.319C>T (p.R107C) alteration is located in coding exon 3 of the ACADS gene. This alteration results from a C to T substitution at nucleotide position 319, causing the arginine (R) at amino acid position 107 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD) database, the ACADS c.319C>T alteration was observed in 0.09% (219/251062) of total alleles studied, with a frequency of 1.88% (182/9668) in the Ashkenazi Jewish subpopulation. This alteration has been reported in the homozygous and compound heterozygous states in patients with short-chain acyl-CoA dehydrogenase deficiency and is a common mutation with an estimated carrier frequency of 1 in 15 in the Ashkenazi Jewish population (Naito, 1990; Tein, 2008; Pedersen, 2008). This amino acid position is highly conserved in available vertebrate species. In vitro functional expression studies showed that the c.319C>T mutant protein was unable to form a functional tetramer resulting in a decreased amount of SCAD protein, loss of enzyme activity, and increased oxidative stress (Tein, 2008; Schmidt, 2011; Edhager, 2014). The p.R107C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at