NM_000017.4(ACADS):c.274G>T (p.Gly92Cys) AND Deficiency of butyryl-CoA dehydrogenase

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000004031.8

Allele description [Variation Report for NM_000017.4(ACADS):c.274G>T (p.Gly92Cys)]

NM_000017.4(ACADS):c.274G>T (p.Gly92Cys)

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.274G>T (p.Gly92Cys)

Other names:

G68C

HGVS:

NC_000012.12:g.120737049G>T
NG_007991.1:g.16282G>T
NM_000017.4:c.274G>TMANE SELECT
NM_001302554.2:c.274G>T
NP_000008.1:p.Gly92Cys
NP_001289483.1:p.Gly92Cys
NC_000012.11:g.121174852G>T
NM_000017.3:c.274G>T
P16219:p.Gly92Cys

Protein change:

G92C; GLY68CYS

Links:

UniProtKB: P16219#VAR_000311; OMIM: 606885.0003; dbSNP: rs121908004

NCBI 1000 Genomes Browser:

rs121908004

Molecular consequence:

NM_000017.4:c.274G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001302554.2:c.274G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of butyryl-CoA dehydrogenase (ACADSD)
Synonyms:: ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF; Lipid-storage myopathy secondary to short chain acyl CoA dehydrogenase deficiency; SCAD DEFICIENCY, MILD
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
SCV000024197	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000963015	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9499414, 14506246, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024197

OMIM

no assertion criteria provided

Pathogenic
(Apr 1, 1998)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000963015

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Citations

PubMed

Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic a...

Gregersen N, Winter VS, Corydon MJ, Corydon TJ, Rinaldo P, Ribes A, Martinez G, Bennett MJ, Vianey-Saban C, Bhala A, Hale DE, Lehnert W, Kmoch S, Roig M, Riudor E, Eiberg H, Andresen BS, Bross P, Bolund LA, Kølvraa S.

Hum Mol Genet. 1998 Apr;7(4):619-27.

PubMed [citation]

PMID:: 9499414

Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency.

Pedersen CB, Bross P, Winter VS, Corydon TJ, Bolund L, Bartlett K, Vockley J, Gregersen N.

J Biol Chem. 2003 Nov 28;278(48):47449-58. Epub 2003 Sep 23.

PubMed [citation]

PMID:: 14506246

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000024197.1

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

Description

Gregersen et al. (1998) characterized 3 disease-causing mutations (confirmed by lack of enzyme activity after expression in COS-7 cells) in 2 patients with SCAD deficiency (201470). One patient was a compound heterozygote for 2 mutations, 274G-T and 529T-C, resulting in gly68-to-cys and trp153-to-arg amino acid substitutions, respectively.

#	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 Invitae, SCV000963015.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 92 of the ACADS protein (p.Gly92Cys). This variant is present in population databases (rs121908004, gnomAD 0.01%). This missense change has been observed in individual(s) with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 9499414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3827). 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) has been performed at Invitae 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. Experimental studies have shown that this missense change affects ACADS function (PMID: 9499414, 14506246). 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.

#	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

Last Updated: Feb 20, 2024

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