NM_000016.5(ACADM):c.734C>T (p.Ser245Leu) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 5, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000003781.5

Allele description [Variation Report for NM_000016.5(ACADM):c.734C>T (p.Ser245Leu)]

NM_000016.5(ACADM):c.734C>T (p.Ser245Leu)

Gene:
ACADM:acyl-CoA dehydrogenase medium chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p31.1
Genomic location:
Preferred name:
NM_000016.5(ACADM):c.734C>T (p.Ser245Leu)
Other names:
S220L
HGVS:
  • NC_000001.11:g.75749444C>T
  • NG_007045.2:g.30087C>T
  • NM_000016.5:c.734C>T
  • NM_001127328.2:c.746C>T
  • NM_001286042.1:c.626C>T
  • NM_001286043.1:c.833C>T
  • NM_001286044.1:c.167C>T
  • NP_000007.1:p.Ser245Leu
  • NP_000007.1:p.Ser245Leu
  • NP_000007.1:p.Ser245Leu
  • NP_001120800.1:p.Ser249Leu
  • NP_001272971.1:p.Ser209Leu
  • NP_001272972.1:p.Ser278Leu
  • NP_001272973.1:p.Ser56Leu
  • LRG_838t1:c.734C>T
  • LRG_838:g.30087C>T
  • LRG_838p1:p.Ser245Leu
  • NC_000001.10:g.76215129C>T
  • NM_000016.4:c.734C>T
  • P11310:p.Ser245Leu
Protein change:
S209L; SER220LEU
Links:
UniProtKB: P11310#VAR_013699; OMIM: 607008.0012; dbSNP: rs121434281
NCBI 1000 Genomes Browser:
rs121434281
Molecular consequence:
  • NM_000016.5:c.734C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127328.2:c.746C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286042.1:c.626C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286043.1:c.833C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286044.1:c.167C>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000023946OMIMno assertion criteria providedPathogenic
(May 1, 2001)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000792652Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 5, 2017)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001199349Invitaecriteria provided, single submitter
Pathogenic
(Nov 5, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Quantitative liquid chromatography coupled with tandem mass spectrometry analysis of urinary acylglycines: application to the diagnosis of inborn errors of metabolism.

Ombrone D, Salvatore F, Ruoppolo M.

Anal Biochem. 2011 Oct 1;417(1):122-8. doi: 10.1016/j.ab.2011.05.042. Epub 2011 Jun 1.

PubMed [citation]
PMID:
21704015

Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.

Smith EH, Thomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D.

Mol Genet Metab. 2010 Jul;100(3):241-50. doi: 10.1016/j.ymgme.2010.04.001. Epub 2010 Apr 8.

PubMed [citation]
PMID:
20434380
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000023946.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

This mutation has also been called SER245LEU (S245L), based on the precursor protein.

In a patient with MCAD deficiency (201450), Zschocke et al. (2001) found a homozygous C-to-T transition at nucleotide 734 in exon 9 of the ACADM gene, resulting in a ser220-to-leu (S220L) mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000792652.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001199349.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces serine with leucine at codon 245 of the ACADM protein (p.Ser245Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs121434281, ExAC 0.004%). This variant has been reported in the literature in several individuals with biochemical profiles diagnostic for MCAD deficiency (PMID: 11409868, 23509891, 20434380, 22683754). ClinVar contains an entry for this variant (Variation ID: 3598). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 18, 2021

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