NM_000016.6(ACADM):c.347G>A (p.Cys116Tyr) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Nov 14, 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:: RCV000211454.18

Allele description [Variation Report for NM_000016.6(ACADM):c.347G>A (p.Cys116Tyr)]

NM_000016.6(ACADM):c.347G>A (p.Cys116Tyr)

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.347G>A (p.Cys116Tyr)

HGVS:

NC_000001.11:g.75733588G>A
NG_007045.2:g.14231G>A
NM_000016.6:c.347G>AMANE SELECT
NM_001127328.3:c.359G>A
NM_001286042.2:c.239G>A
NM_001286043.2:c.446G>A
NM_001286044.2:c.-100+666G>A
NP_000007.1:p.Cys116Tyr
NP_000007.1:p.Cys116Tyr
NP_001120800.1:p.Cys120Tyr
NP_001272971.1:p.Cys80Tyr
NP_001272972.1:p.Cys149Tyr
LRG_838t1:c.347G>A
LRG_838:g.14231G>A
LRG_838p1:p.Cys116Tyr
NC_000001.10:g.76199273G>A
NM_000016.4:c.347G>A
NM_000016.5:c.347G>A
P11310:p.Cys116Tyr

Protein change:

C116Y

Links:

UniProtKB: P11310#VAR_015955; dbSNP: rs875989859

NCBI 1000 Genomes Browser:

rs875989859

Molecular consequence:

NM_001286044.2:c.-100+666G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000016.6:c.347G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.359G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.239G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.446G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000268452	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]
SCV000792310	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Oct 4, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20567907, 9158144, 19649258 Citation Link,
SCV000933584	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9158144, 19649258, 20567907, 29285339, 28492532
SCV002092818	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 16, 2017)	germline	clinical testing
SCV004037994	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20567907, 9158144, 29285339, 19649258 Citation Link,
SCV004213044	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 14, 2023)	unknown	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications.

Al-Hassnan ZN, Imtiaz F, Al-Amoudi M, Rahbeeni Z, Al-Sayed M, Al-Owain M, Al-Zaidan H, Al-Odaib A, Rashed MS.

J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S263-7. doi: 10.1007/s10545-010-9143-1. Epub 2010 Jun 22.

PubMed [citation]

PMID:: 20567907

See all PubMed Citations (6)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268452.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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)	2	not provided	not provided	not provided

From Counsyl, SCV000792310.1

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

#	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, SCV000933584.6

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

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 116 of the ACADM protein (p.Cys116Tyr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 9158144, 19649258, 20567907, 29285339). This variant is also known as C91Y. ClinVar contains an entry for this variant (Variation ID: 226068). 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) performed at Invitae indicates that this missense variant is expected to disrupt ACADM protein function with a positive predictive value of 80%. 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., SCV002092818.1

#	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, SCV004037994.1

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

Description

Variant summary: ACADM c.347G>A (p.Cys116Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251440 control chromosomes. c.347G>A has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with biochemically and clinically consistent features of Medium Chain Acyl-CoA Dehydrogenase Deficiency (example, Andresen_1997, ter Veld_2009, Al-Hassnan_2010, Dobrowlski_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20567907, 9158144, 29285339, 19649258). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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

From Baylor Genetics, SCV004213044.1

#	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 20, 2024

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