rs61732144

Positions:

• chr12-120737094-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PS1 PM1 PP3 PP5_Very_Strong BP4

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 same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 1.47

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_000017.4 (ACADS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 421618
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000017.4
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• PP5: Variant 12-120737094-C-T is Pathogenic according to our data. Variant chr12-120737094-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120737094-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.058556437). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4	c.319C>T	p.Arg107Cys	missense_variant	3/10	ENST00000242592.9
ACADS	NM_001302554.2	c.319C>T	p.Arg107Cys	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9	c.319C>T	p.Arg107Cys	missense_variant	3/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2	c.319C>T	p.Arg107Cys	missense_variant	3/10	2
ACADS	ENST00000539690.1	n.431C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152246 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000970 AC: 213 AN: 219678 Hom.: 2 AF XY: 0.000901 AC XY: 107 AN XY: 118742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000629

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000184

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.000499 AC: 721 AN: 1445256 Hom.: 7 Cov.: 31 AF XY: 0.000506 AC XY: 363 AN XY: 717420

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000937

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000718

Gnomad4 FIN exome AF: 0.0000580

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152246 Hom.: 2 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.000586

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000786 AC: 95

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:12 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 18, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2023	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 29, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	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). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 10, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 16, 2019	PS3, PS4_moderate, PM2, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2021

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.059	T;T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MVP		1.0
MPC		0.91
ClinPred		0.51	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61732144; hg19: chr12-121174897;