NM_000016.6(ACADM):c.820A>G (p.Met274Val) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 17, 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:: RCV002938655.5

Allele description [Variation Report for NM_000016.6(ACADM):c.820A>G (p.Met274Val)]

NM_000016.6(ACADM):c.820A>G (p.Met274Val)

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.820A>G (p.Met274Val)

HGVS:

NC_000001.11:g.75749530A>G
NG_007045.2:g.30173A>G
NM_000016.6:c.820A>GMANE SELECT
NM_001127328.3:c.832A>G
NM_001286042.2:c.712A>G
NM_001286043.2:c.919A>G
NM_001286044.2:c.253A>G
NP_000007.1:p.Met274Val
NP_000007.1:p.Met274Val
NP_001120800.1:p.Met278Val
NP_001272971.1:p.Met238Val
NP_001272972.1:p.Met307Val
NP_001272973.1:p.Met85Val
LRG_838t1:c.820A>G
LRG_838:g.30173A>G
LRG_838p1:p.Met274Val
NC_000001.10:g.76215215A>G
NM_000016.5:c.820A>G

Protein change:

M238V

Molecular consequence:

NM_000016.6:c.820A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.832A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.712A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.919A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.253A>G - 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
SCV003271299	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27856190, 26947917, 28492532
SCV004213232	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 17, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003271299

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004213232

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 17, 2024)

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	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

Screening of MCAD deficiency in Japan: 16years' experience of enzymatic and genetic evaluation.

Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Hata I, Shigematsu Y, Kobayashi M.

Mol Genet Metab. 2016 Dec;119(4):322-328. doi: 10.1016/j.ymgme.2016.10.007. Epub 2016 Oct 21.

PubMed [citation]

PMID:: 27856190

Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan.

Hara K, Tajima G, Okada S, Tsumura M, Kagawa R, Shirao K, Ohno Y, Yasunaga S, Ohtsubo M, Hata I, Sakura N, Shigematsu Y, Takihara Y, Kobayashi M.

Mol Genet Metab. 2016 May;118(1):9-14. doi: 10.1016/j.ymgme.2015.12.011. Epub 2015 Dec 29.

PubMed [citation]

PMID:: 26947917

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003271299.2

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

Description

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 274 of the ACADM protein (p.Met274Val). This variant is present in population databases (rs751163688, gnomAD 0.007%). This missense change has been observed in individual(s) with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 26947917, 27856190). This variant is also known as c.820A>G (M249V). ClinVar contains an entry for this variant (Variation ID: 2059928). 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%. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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, SCV004213232.2

#	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

Last Updated: Sep 29, 2024

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