NM_000016.6(ACADM):c.946-6T>G AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (8 submissions)
Last evaluated:: Mar 25, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000674990.21

Allele description [Variation Report for NM_000016.6(ACADM):c.946-6T>G]

NM_000016.6(ACADM):c.946-6T>G

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

NM_000016.6(ACADM):c.946-6T>G

HGVS:

NC_000001.11:g.75761116T>G
NG_007045.2:g.41759T>G
NM_000016.6:c.946-6T>GMANE SELECT
NM_001127328.3:c.958-6T>G
NM_001286042.2:c.838-6T>G
NM_001286043.2:c.1045-6T>G
NM_001286044.2:c.379-6T>G
LRG_838t1:c.946-6T>G
LRG_838:g.41759T>G
NC_000001.10:g.76226801T>G
NM_000016.4:c.946-6T>G
NM_000016.5:c.946-6T>G

Links:

dbSNP: rs765793260

NCBI 1000 Genomes Browser:

rs765793260

Molecular consequence:

NM_000016.6:c.946-6T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001127328.3:c.958-6T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001286042.2:c.838-6T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001286043.2:c.1045-6T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001286044.2:c.379-6T>G - 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
SCV000800411	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Jun 4, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22166308, 22542437 Citation Link,
SCV001420435	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 29, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22542437, 23028790, 24966162, 28492532
SCV002092858	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Aug 21, 2017)	germline	clinical testing
SCV002600500	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32778825, 22166308 Citation Link,
SCV003822452	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004047231	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004213221	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004806052	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	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

MCAD deficiency in Denmark.

Andresen BS, Lund AM, Hougaard DM, Christensen E, Gahrn B, Christensen M, Bross P, Vested A, Simonsen H, Skogstrand K, Olpin S, Brandt NJ, Skovby F, Nørgaard-Pedersen B, Gregersen N.

Mol Genet Metab. 2012 Jun;106(2):175-88. doi: 10.1016/j.ymgme.2012.03.018. Epub 2012 Apr 4.

PubMed [citation]

PMID:: 22542437

Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants.

Sturm M, Herebian D, Mueller M, Laryea MD, Spiekerkoetter U.

PLoS One. 2012;7(9):e45110. doi: 10.1371/journal.pone.0045110. Epub 2012 Sep 17.

PubMed [citation]

PMID:: 23028790
PMCID:: PMC3444485

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000800411.1

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

#	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, SCV001420435.5

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

Description

This sequence change falls in intron 10 of the ACADM gene. It does not directly change the encoded amino acid sequence of the ACADM protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 41 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs765793260, gnomAD 0.07%). This variant has been observed in individual(s) with MCAD deficiency (Invitae). 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: 558685). Studies have shown that this variant results in the activation of a cryptic splice site in exon 11 (PMID: 22542437). This variant disrupts the p.Met328 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23028790, 24966162; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Natera, Inc., SCV002092858.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600500.1

#	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.946-6T>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Four predict the variant creates a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-05 in 249872 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (8e-05 vs 0.0054), allowing no conclusion about variant significance. c.946-6T>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Oerton_2011, Adhikari_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=1). 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 Revvity Omics, Revvity, SCV003822452.2

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047231.1

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

Description

The splice variant c.946-6T>G in ACADM gene has been reported previously in homozygous/ compound heterozygous state in patients affected with MCAD deficiency, in at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (Andresen BS et al). The c.946-6T>G variant is reported with the allele frequency of 0.008004% in gnomAD Exome and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing (Andresen BS et al). 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004213221.2

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806052.1

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

Last Updated: Sep 29, 2024

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