NM_000016.6(ACADM):c.449_452del (p.Thr150fs) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Mar 20, 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:: RCV000169427.31

Allele description [Variation Report for NM_000016.6(ACADM):c.449_452del (p.Thr150fs)]

NM_000016.6(ACADM):c.449_452del (p.Thr150fs)

Gene:

ACADM:acyl-CoA dehydrogenase medium chain [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_000016.6(ACADM):c.449_452del (p.Thr150fs)

HGVS:

NC_000001.11:g.75734852_75734855del
NG_007045.2:g.15495_15498del
NM_000016.6:c.449_452delMANE SELECT
NM_001127328.3:c.461_464del
NM_001286042.2:c.341_344del
NM_001286043.2:c.548_551del
NM_001286044.2:c.-100+1930_-100+1933del
NP_000007.1:p.Thr150fs
NP_000007.1:p.Thr150fs
NP_001120800.1:p.Thr154fs
NP_001272971.1:p.Thr114fs
NP_001272972.1:p.Thr183fs
LRG_838t1:c.449_452del
LRG_838:g.15495_15498del
LRG_838p1:p.Thr150fs
NC_000001.10:g.76200534_76200537del
NC_000001.10:g.76200537_76200540del
NM_000016.4:c.446_449delTGAC
NM_000016.4:c.449_452delCTGA
NM_000016.5:c.449_452del
NM_000016.5:c.449_452delCTGA
NM_000016.6:c.449_452delCTGAMANE SELECT

Protein change:

T114fs

Links:

OMIM: 607008.0016; dbSNP: rs786204642

NCBI 1000 Genomes Browser:

rs786204642

Molecular consequence:

NM_000016.6:c.449_452del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127328.3:c.461_464del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001286042.2:c.341_344del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001286043.2:c.548_551del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001286044.2:c.-100+1930_-100+1933del - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Medium-chain acyl-coenzyme A dehydrogenase deficiency (ACADMD)
Synonyms:: CARNITINE DEFICIENCY SECONDARY TO MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY; MCADD; Medium chain acyl-CoA dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0008721; MedGen: C0220710; Orphanet: 42; OMIM: 201450

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220837	Counsyl	no assertion criteria provided	Pathogenic (Feb 22, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000268448	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000630287	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16121256, 20434380, 15915086, 19064330, 22796001, 25503862, 28492532
SCV001361312	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 9, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15915086, 19699128 Citation Link,
SCV001739490	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 28, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001786673	OMIM	no assertion criteria provided	Pathogenic (Apr 4, 2024)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002092829	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV003838957	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	no assertion criteria provided	Likely pathogenic	maternal	clinical testing
SCV004212147	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 20, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004800880	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
East asia	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Han	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Medium-chain acyl-CoA dehydrogenase deficiency in gene-targeted mice.

Tolwani RJ, Hamm DA, Tian L, Sharer JD, Vockley J, Rinaldo P, Matern D, Schoeb TR, Wood PA.

PLoS Genet. 2005 Aug;1(2):e23. Epub 2005 Aug 19.

PubMed [citation]

PMID:: 16121256
PMCID:: PMC1189074

Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.

Smith EH, Thomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D.

Mol Genet Metab. 2010 Jul;100(3):241-50. doi: 10.1016/j.ymgme.2010.04.001. Epub 2010 Apr 8.

PubMed [citation]

PMID:: 20434380

See all PubMed Citations (10)

PMC

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Details of each submission

From Counsyl, SCV000220837.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268448.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing (GTR000500814.1)	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	(GTR000500814.1)	1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000630287.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Thr150Argfs*4) in the ACADM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). This variant is present in population databases (rs757500332, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with MCAD deficiency (PMID: 15915086, 19064330, 22796001, 25503862). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189036). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361312.1

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

Description

Variant summary: ACADM c.449_452delCTGA (p.Thr150ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 251336 control chromosomes (gnomAD). c.449_452delCTGA has been reported in the literature in compound heterozygous and homozygous individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Ensenauer_2005, Purevsuren_2009). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. 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 Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital, SCV001739490.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East asia	1	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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From OMIM, SCV001786673.2

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

Description

In a cohort of 31 Japanese patients with MCAD deficiency and 7 Japanese carriers of the disorder (ACADMD; 201450), Tajima et al. (2016) found that the most prevalent mutation was a 4-bp deletion (c.449_452delCTGA) in the ACADM gene, predicted to result in a frameshift and premature termination (Thr150Argfs). The mutation, which was found by direct sequencing of the gene, was identified in 25 ACADM alleles of 22 individuals from 19 families. Analyses in patient lymphocytes showed that the mutation resulted in abolished ACADM enzyme activity.

#	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 Natera, Inc., SCV002092829.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University, SCV003838957.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		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	maternal	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004212147.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital, SCV004800880.1

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

Description

PVS1+PM2_P+PM3+PP4

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

Last Updated: Sep 29, 2024

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