12-120739168-C-T

Position:

chr12-120739168-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 5.52

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

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	Protein	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.1058C>T	p.Ser353Leu	missense_variant	9/10	ENST00000242592.9	NP_000008.1	P16219E5KSD5
ACADS	NM_001302554.2 linkuse as main transcript	c.1046C>T	p.Ser349Leu	missense_variant	9/10		NP_001289483.1	P16219E9PE82B4DUH1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9 linkuse as main transcript	c.1058C>T	p.Ser353Leu	missense_variant	9/10	1	NM_000017.4	ENSP00000242592.4		P16219
ACADS	ENST00000411593.2 linkuse as main transcript	c.1046C>T	p.Ser349Leu	missense_variant	9/10	2		ENSP00000401045.2		E9PE82

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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:

AN:

246882

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

134618

show subpopulations

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.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

726694

show subpopulations

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:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74328

show subpopulations

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.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 06, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 15, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
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	MGZ Medical Genetics Center	Apr 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Genome-Nilou Lab	Nov 07, 2021	- -
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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 21, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
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	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

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Uncertain

0.66

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over