rs537072819

Variant names:

• chr12-120739365-C-T
• rs537072819
• NM_000017.4:c.1156C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000017.4(ACADS):​c.1156C>T​(p.Arg386Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000589 in 1,612,986 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 4.53
• Publications: 5 publications found

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]

ACADS Gene-Disease associations (from GenCC):

• short chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, ClinGen

ENSG00000255946 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000017.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120739366-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1418253.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.58444 (below the threshold of 3.09). Trascript score misZ: 0.78549 (below the threshold of 3.09). GenCC associations: The gene is linked to short chain acyl-CoA dehydrogenase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000017.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	NM_000017.4	MANE Select	c.1156C>T	p.Arg386Cys	missense	Exon 10 of 10	NP_000008.1
	ACADS	NM_001302554.2		c.1144C>T	p.Arg382Cys	missense	Exon 10 of 10	NP_001289483.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	ENST00000242592.9	TSL:1 MANE Select	c.1156C>T	p.Arg386Cys	missense	Exon 10 of 10	ENSP00000242592.4
	ACADS	ENST00000411593.2	TSL:2	c.1144C>T	p.Arg382Cys	missense	Exon 10 of 10	ENSP00000401045.2
	ENSG00000255946	ENST00000724268.1		n.305-9077G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000564 AC: 14 AN: 248252 AF XY: 0.0000444

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1460644 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 39 AN XY: 726650

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000648 AC: 72 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74494

African (AFR) AF: 0.0000481 AC: 2 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000590 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:1 Uncertain:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 07, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the ACADS protein (p.Arg386Cys). This variant is present in population databases (rs537072819, gnomAD 0.02%). This missense change has been observed in individuals with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 16906473; internal data). This variant is also known as Arg362Cys. ClinVar contains an entry for this variant (Variation ID: 203566). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADS protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Aug 29, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not specified Uncertain:1

Jun 06, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADS c.1156C>T (p.Arg386Cys) results in a non-conservative amino acid change located in the 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 5.6e-05 in 248252 control chromosomes (gnomAD, v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1156C>T has been reported in the literature as a biallelic compound heterozygous genotype in several individuals affected with features of short-chain acyl-CoA dehydrogenase (SCAD) deficiency/Deficiency Of Butyryl-CoA Dehydrogenase (e.g., Geregersen_2008, Wang_2020, Maguolo_2020, Jiang_2020). In some individuals, it was reported in trans with the commonly reported ACADS susceptibility allele c.625G>A (p.Gly209Ser), which is classified as benign/likely benign in the ClinVar database (Merinero_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18836889, 33391346, 32793418, 16906473, 32447334). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: four submitters classified the variant as uncertain significance, and one submitter classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

not provided Uncertain:1

Jul 20, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16906473, 32447334, 18836889, 33391346)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		Loss of disorder (P = 0.0462)
MVP		1.0
MPC		0.91
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs537072819; hg19: chr12-121177168; COSMIC: COSV54369302; COSMIC: COSV54369302;