rs28941773

chr12-120739168-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000017.4(ACADS):c.1058C>T(p.Ser353Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,612,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S353P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.52

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 16 ACMG points.

• PM1: In a helix (size 25) in uniprot entity ACADS_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000017.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 12-120739168-C-T is Pathogenic according to our data. Variant chr12-120739168-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120739168-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4	c.1058C>T	p.Ser353Leu	missense_variant	9/10	ENST00000242592.9
ACADS	NM_001302554.2	c.1046C>T	p.Ser349Leu	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9	c.1058C>T	p.Ser353Leu	missense_variant	9/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2	c.1046C>T	p.Ser349Leu	missense_variant	9/10	2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000198 AC: 49 AN: 246882 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000424

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000222 AC: 325 AN: 1460738 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 156 AN XY: 726694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000326 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2023	Variant summary: ACADS c.1058C>T (p.Ser353Leu) results in a non-conservative amino acid change in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) 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 0.0002 in 246882 control chromosomes in GnomAD. c.1058C>T has been reported in the literature in individuals affected with Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (example: Corydon_2001, Sadat_2020, vanMaldegem_2006). This variant has been reported in compound heterozygous state with c.529T>C/p.Trp177Arg (P/LP in ClinVar) in settings of newborn screening for Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (Sadat_2020). It was found in 8 of 20 patients, all of Dutch ancestry, suggesting a founder effect of this variant in Dutch (vanMaldegem_2006). However, in most cases, this variant was the only disease-causing variant in ACADS that had been found, and the secondary variant, if reported, was usually c.625G>A (p.Gly209Ser, a common susceptibility variant classified as Benign/LB in ClinVar). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Corydon_ 2001). Impaired ACADS tetramer formation and Chaperone complex formation, and aggregation tendency were also reported (Pedersen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 11134486, 28532786, 31980526, 18523805, 31813752, 19800078). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 14, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 353 of the ACADS protein (p.Ser353Leu). This variant is present in population databases (rs28941773, gnomAD 0.04%). This missense change has been observed in individual(s) with SCAD deficiency (PMID: 11134486, 18523805, 19800078; Invitae). ClinVar contains an entry for this variant (Variation ID: 3836). 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: 11134486, 18523805). This variant disrupts the p.Ser353 amino acid residue in ACADS. Other variant(s) that disrupt this residue have been observed in individuals with ACADS-related conditions (PMID: 22424739), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 19, 2018	The ACADS c.1058C>T (p.Ser353Leu) missense variant has been reported in two studies in which it is identified in at least seven probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency, all in a compound heterozygous state with the common susceptibility allele, c.625C>T (Corydon et al. 2001; Van Maldegem et al. 2010). The p.Ser353Leu variant was reported in 5 of 959 controls in a heterozygous state and in one control along with the c.625C>T variant where zygosity is not confirmed (Corydon et al. 2001; Van Maldegem et al. 2011). The p.Ser353Leu is also reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functionally, SCAD enzyme activity was significantly reduced in E. coli expressing the p.Ser329Leu variant protein compared to wild type (Corydon et al. 2001). Of note, individuals with SCAD deficiency show variable expressivity of this condition, even among affected family members, and some individuals with a molecular diagnosis are asymptomatic into adulthood. Based on the collective evidence, the p.Ser353Leu variant is classified as pathogenic for short-chain acyl-coA dehydrogenase 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	Baylor Genetics	Aug 06, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 21, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2023	Published functional studies demonstrate a damaging effect (Corydon et al., 2001; Pedersen et al., 2008); This variant is associated with the following publications: (PMID: 11134486, 16926354, 28532786, 18523805, 28263315, 21500142, 31980526, 34426522, 31813752) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 12, 2017	The ACADS p.Ser353Leu variant (rs28941773) has been reported in two individuals with a diagnosis of short-chain acyl-CoA dehydrogenase (SCAD) deficiency who also had a common risk factor variant (Corydon 2001 and Dessein 2017). Furthermore, functional studies show that the ACADS protein harboring the p.Ser353Leu variant does not have detectable enzymatic activity compared to wild type when expressed in bacteria (Corydon 2001). The p.Ser353Leu variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.044% in the non-Finnish European population (identified in 54 out of 123,600 chromosomes), which is consistent with a recessive carrier frequency. This variant is also present in the ClinVar database (Variant ID: 3836). Therefore, based on the available evidence, the p.Ser353Leu variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.90
MVP		0.99
MPC		0.72
ClinPred		0.95	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28941773; hg19: chr12-121176971; COSMIC: COSV54369151; COSMIC: COSV54369151;