NM_000016.6(ACADM):c.843A>T (p.Arg281Ser) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 16, 2022
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:: RCV000665026.12

Allele description [Variation Report for NM_000016.6(ACADM):c.843A>T (p.Arg281Ser)]

NM_000016.6(ACADM):c.843A>T (p.Arg281Ser)

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.843A>T (p.Arg281Ser)

HGVS:

NC_000001.11:g.75749553A>T
NG_007045.2:g.30196A>T
NM_000016.6:c.843A>TMANE SELECT
NM_001127328.3:c.855A>T
NM_001286042.2:c.735A>T
NM_001286043.2:c.942A>T
NM_001286044.2:c.276A>T
NP_000007.1:p.Arg281Ser
NP_000007.1:p.Arg281Ser
NP_001120800.1:p.Arg285Ser
NP_001272971.1:p.Arg245Ser
NP_001272972.1:p.Arg314Ser
NP_001272973.1:p.Arg92Ser
LRG_838t1:c.843A>T
LRG_838:g.30196A>T
LRG_838p1:p.Arg281Ser
NC_000001.10:g.76215238A>T
NM_000016.4:c.843A>T
NM_000016.5:c.843A>T

Protein change:

R245S

Links:

dbSNP: rs780504551

NCBI 1000 Genomes Browser:

rs780504551

Molecular consequence:

NM_000016.6:c.843A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.855A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.735A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.942A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001286044.2:c.276A>T - 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
SCV000789080	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 5, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15915086, 22796001, 26947917 Citation Link,
SCV000930743	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 16, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15915086, 26947917, 27856190, 28492532
SCV002092853	Natera, Inc.	no assertion criteria provided	Pathogenic (May 3, 2017)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000789080

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Jan 5, 2017)

unknown

clinical testing

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

Citation Link,

SCV000930743

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 16, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002092853

Natera, Inc.

no assertion criteria provided

Pathogenic
(May 3, 2017)

germline

clinical testing

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

Clinical and molecular aspects of Japanese children with medium chain acyl-CoA dehydrogenase deficiency.

Purevsuren J, Hasegawa Y, Fukuda S, Kobayashi H, Mushimoto Y, Yamada K, Takahashi T, Fukao T, Yamaguchi S.

Mol Genet Metab. 2012 Sep;107(1-2):237-40. doi: 10.1016/j.ymgme.2012.06.010. Epub 2012 Jun 26.

PubMed [citation]

PMID:: 22796001

Genotypic differences of MCAD deficiency in the Asian population: novel genotype and clinical symptoms preceding newborn screening notification.

Ensenauer R, Winters JL, Parton PA, Kronn DF, Kim JW, Matern D, Rinaldo P, Hahn SH.

Genet Med. 2005 May-Jun;7(5):339-43.

PubMed [citation]

PMID:: 15915086

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000789080.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000930743.6

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

Description

This variant is present in population databases (rs780504551, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). 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. ClinVar contains an entry for this variant (Variation ID: 550313). This variant is also known as p.R256S. This missense change has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 15915086, 26947917, 27856190). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 281 of the ACADM protein (p.Arg281Ser).

#	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., SCV002092853.1

#	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

Last Updated: Sep 29, 2024

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