NM_000017.4(ACADS):c.136C>T (p.Arg46Trp) AND Deficiency of butyryl-CoA dehydrogenase

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Nov 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004029.32

Allele description [Variation Report for NM_000017.4(ACADS):c.136C>T (p.Arg46Trp)]

NM_000017.4(ACADS):c.136C>T (p.Arg46Trp)

Gene:

ACADS:acyl-CoA dehydrogenase short chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_000017.4(ACADS):c.136C>T (p.Arg46Trp)

Other names:

p.R46W:CGG>TGG

HGVS:

NC_000012.12:g.120727115C>T
NG_007991.1:g.6348C>T
NM_000017.4:c.136C>TMANE SELECT
NM_001302554.2:c.136C>T
NP_000008.1:p.Arg46Trp
NP_001289483.1:p.Arg46Trp
NC_000012.11:g.121164918C>T
NM_000017.2:c.136C>T
NM_000017.3:c.136C>T
NM_001302554.2:c.136C>T
P16219:p.Arg46Trp

Protein change:

R46W; ARG46TRP

Links:

UniProtKB: P16219#VAR_000310; OMIM: 606885.0001; dbSNP: rs121908003

NCBI 1000 Genomes Browser:

rs121908003

Molecular consequence:

NM_000017.4:c.136C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001302554.2:c.136C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of butyryl-CoA dehydrogenase (ACADSD)
Synonyms:: ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF; ACADS DEFICIENCY; SCADH DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008722; MedGen: C0342783; Orphanet: 26792; OMIM: 201470

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024195	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1989)	germline	literature only	PubMed (1) [See all records that cite this PMID] Naito, E., Indo, Y., Tanaka, K. Short chain acyl-CoA dehydrogenase (SCAD) deficiency: demonstration of molecular heterogeneity and identification of point mutations. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A208, 1989.,
SCV000220171	Counsyl	no assertion criteria provided	Likely pathogenic (Mar 16, 2014)	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 14506246, 9582344
SCV000940838	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 19, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1692038, 18523805, 28454995, 9582344, 14506246, 28492532
SCV001133031	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Likely pathogenic (Sep 26, 2019)	germline	clinical testing
SCV002792455	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003808394	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841754	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9582344, 1692038, 14506246, 28454995, 25741868
SCV004805177	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004813527	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 20, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28454995, 18523805, 9582344, 1692038, 14506246 Citation Link,
SCV005873759	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	criteria provided, single submitter (Submitter's publication)	Likely pathogenic (Aug 11, 2021)	unknown	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only
South East Asian	unknown	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Short chain acyl-coenzyme A dehydrogenase (SCAD) deficiency. Immunochemical demonstration of molecular heterogeneity due to variant SCAD with differing stability.

Naito E, Indo Y, Tanaka K.

J Clin Invest. 1989 Nov;84(5):1671-4.

PubMed [citation]

PMID:: 2808706
PMCID:: PMC304035

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000024195.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with SCAD deficiency (201470), Naito et al. (1989, 1990) found evidence of compound heterozygosity. One chromosome carried a C-to-T transition in nucleotide 136 which altered arg46 to trp. See 606885.0002 for the mutation in the other allele. The cell line studied was from the patient reported by Naito et al. (1989).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000220171.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000940838.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the ACADS protein (p.Arg46Trp). This variant is present in population databases (rs121908003, gnomAD 0.08%). This missense change has been observed in individuals with SCAD deficiency (PMID: 1692038, 18523805, 28454995). This variant is also known as R22W. ClinVar contains an entry for this variant (Variation ID: 3825). 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 95%. Experimental studies have shown that this missense change affects ACADS function (PMID: 9582344, 14506246). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001133031.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002792455.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003808394.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003841754.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 14506246, 9582344). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003825). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 1692038, 28454995). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004805177.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813527.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: ACADS c.136C>T (p.Arg46Trp) results in a non-conservative amino acid change located in the acyl-CoA dehydrogenase/oxidase, 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 0.00016 in 251496 control chromosomes (gnomAD). c.136C>T has been reported in the literature as a biallelic genotype in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (e.g. Naito_1990, Pedersen_2008, Alfares_2017). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (Corydon_1998, Pedersen_2003). The results showed that the variant primarily existed as an insoluble protein, likely due to protein misfolding, and resulted in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 28454995, 9582344, 1692038, 18523805, 14506246). ClinVar contains an entry for this variant (Variation ID: 3825). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare, SCV005873759.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South East Asian	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 5, 2025

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