NM_000016.6(ACADM):c.424AAG[2] (p.Lys144del) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Sep 3, 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:: RCV000211510.15

Allele description [Variation Report for NM_000016.6(ACADM):c.424AAG[2] (p.Lys144del)]

NM_000016.6(ACADM):c.424AAG[2] (p.Lys144del)

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.424AAG[2] (p.Lys144del)

HGVS:

NC_000001.11:g.75734827AAG[2]
NG_007045.2:g.15470AAG[2]
NM_000016.6:c.424AAG[2]MANE SELECT
NM_001127328.3:c.436AAG[2]
NM_001286042.2:c.316AAG[2]
NM_001286043.2:c.523AAG[2]
NM_001286044.2:c.-100+1905AAG[2]
NP_000007.1:p.Lys144del
NP_001120800.1:p.Lys148del
NP_001272971.1:p.Lys108del
NP_001272972.1:p.Lys177del
LRG_838:g.15470AAG[2]
NC_000001.10:g.76200512AAG[2]
NC_000001.10:g.76200512_76200514del
NM_000016.4:c.430_432delAAG
NM_000016.6:c.430_432delMANE SELECT

Protein change:

K108del

Links:

dbSNP: rs875989857

NCBI 1000 Genomes Browser:

rs875989857

Molecular consequence:

NM_000016.6:c.424AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001127328.3:c.436AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001286042.2:c.316AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001286043.2:c.523AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001286044.2:c.-100+1905AAG[2] - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000268445	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001132317	Counsyl	no assertion criteria provided	Likely pathogenic (Mar 7, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27308838, 25940036, 21083904, 20434380, 23028790
SCV001578471	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 20, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20434380, 21083904, 23028790, 31012112, 28492532
SCV004013930	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004210669	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 3, 2023)	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	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

Citations

PubMed

Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing.

Narravula A, Garber KB, Askree SH, Hegde M, Hall PL.

Genet Med. 2017 Jan;19(1):77-82. doi: 10.1038/gim.2016.67. Epub 2016 Jun 16.

PubMed [citation]

PMID:: 27308838

Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening.

Gramer G, Haege G, Fang-Hoffmann J, Hoffmann GF, Bartram CR, Hinderhofer K, Burgard P, Lindner M.

JIMD Rep. 2015;23:101-12. doi: 10.1007/8904_2015_439. Epub 2015 May 5.

PubMed [citation]

PMID:: 25940036
PMCID:: PMC4484909

See all PubMed Citations (8)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268445.1

#	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 Counsyl, SCV001132317.1

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

#	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 Invitae, SCV001578471.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with MCAD deficiency (PMID: 20434380, 21083904, 23028790, 31012112). This variant is present in population databases (rs756277519, gnomAD 0.0009%). This variant, c.430_432del, results in the deletion of 1 amino acid(s) of the ACADM protein (p.Lys144del), but otherwise preserves the integrity of the reading frame.

#	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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV004013930.1

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

Description

PM1, PM2, PM4, PP3, PP5

#	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 Baylor Genetics, SCV004210669.1

#	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: Feb 14, 2024

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