NM_000016.6(ACADM):c.957_958del (p.Ser320fs) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Aug 23, 2023
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:: RCV000410180.16

Allele description [Variation Report for NM_000016.6(ACADM):c.957_958del (p.Ser320fs)]

NM_000016.6(ACADM):c.957_958del (p.Ser320fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_000016.6(ACADM):c.957_958del (p.Ser320fs)

HGVS:

NC_000001.10:g.76226816_76226817del
NC_000001.11:g.75761131AT[1]
NG_007045.2:g.41774AT[1]
NM_000016.6:c.957_958delMANE SELECT
NM_001127328.3:c.969_970del
NM_001286042.2:c.849_850del
NM_001286043.2:c.1056_1057del
NM_001286044.2:c.390_391del
NP_000007.1:p.Ser320fs
NP_001120800.1:p.Ser324fs
NP_001272971.1:p.Ser284fs
NP_001272972.1:p.Ser353fs
NP_001272973.1:p.Ser131fs
LRG_838:g.41774AT[1]
NC_000001.10:g.76226816AT[1]
NC_000001.10:g.76226816_76226817del
NC_000001.10:g.76226818_76226819delAT
NM_000016.4:c.957_958delAT

Protein change:

S131fs

Links:

dbSNP: rs1057517103

NCBI 1000 Genomes Browser:

rs1057517103

Molecular consequence:

NM_000016.6:c.957_958del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127328.3:c.969_970del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001286042.2:c.849_850del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001286043.2:c.1056_1057del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001286044.2:c.390_391del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000486754	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 3, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV002049460	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Mar 8, 2021)	germline	clinical testing	Citation Link,
SCV002238961	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 23, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9158144, 16121256, 20434380, 28492532
SCV004211649	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 8, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	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	clinical testing

Citations

PubMed

The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?

Andresen BS, Bross P, Udvari S, Kirk J, Gray G, Kmoch S, Chamoles N, Knudsen I, Winter V, Wilcken B, Yokota I, Hart K, Packman S, Harpey JP, Saudubray JM, Hale DE, Bolund L, Kølvraa S, Gregersen N.

Hum Mol Genet. 1997 May;6(5):695-707.

PubMed [citation]

PMID:: 9158144

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

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000486754.2

#	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, SCV002049460.1

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

Description

The ACADM c.957_958delAT; p.Ser320IlefsTer5 variant (rs1057517103), also known as 955-956del, is reported in the literature in a homozygous individual affected with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Andresen 1997). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Consistent with this prediction, northern blot analysis of the patient homozygous for this variant demonstrated little to no expression of the variant transcript (Andresen 1997). Based on available information, this variant is considered to be pathogenic. References: Andresen BS et al. The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype? Hum Mol Genet. 1997 May;6(5):695-707.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002238961.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371224). This premature translational stop signal has been observed in individual(s) with MCAD deficiency (PMID: 9158144). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser320Ilefs*5) 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).

#	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 Baylor Genetics, SCV004211649.1

#	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

Last Updated: Sep 29, 2024

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