NM_000016.6(ACADM):c.755T>G (p.Phe252Cys) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(2) (Last evaluated: Jul 30, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000211533.7

Allele description [Variation Report for NM_000016.6(ACADM):c.755T>G (p.Phe252Cys)]

NM_000016.6(ACADM):c.755T>G (p.Phe252Cys)

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.755T>G (p.Phe252Cys)
HGVS:
  • NC_000001.11:g.75749465T>G
  • NG_007045.2:g.30108T>G
  • NM_000016.5:c.755T>G
  • NM_000016.6:c.755T>GMANE SELECT
  • NM_001127328.3:c.767T>G
  • NM_001286042.2:c.647T>G
  • NM_001286043.2:c.854T>G
  • NM_001286044.2:c.188T>G
  • NP_000007.1:p.Phe252Cys
  • NP_000007.1:p.Phe252Cys
  • NP_001120800.1:p.Phe256Cys
  • NP_001272971.1:p.Phe216Cys
  • NP_001272972.1:p.Phe285Cys
  • NP_001272973.1:p.Phe63Cys
  • LRG_838t1:c.755T>G
  • LRG_838:g.30108T>G
  • LRG_838p1:p.Phe252Cys
  • NC_000001.10:g.76215150T>G
  • NM_000016.4:c.755T>G
Protein change:
F216C
Links:
dbSNP: rs780510026
NCBI 1000 Genomes Browser:
rs780510026
Molecular consequence:
  • NM_000016.5:c.755T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000016.6:c.755T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127328.3:c.767T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286042.2:c.647T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286043.2:c.854T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286044.2:c.188T>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000268451ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Feb 20, 2015)
germlineclinical testing

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

SCV000630295Invitaecriteria provided, single submitter
Pathogenic
(Jul 30, 2019)
germlineclinical testing

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

SCV001448920Knight Diagnostic Laboratories, Oregon Health and Sciences Universitycriteria provided, single submitter
Uncertain significance
(Mar 18, 2019)
germlineclinical testing

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

SCV001461469Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot providednot providednot providedclinical 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000268451.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing
(GTR000500814.1)
PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided
(GTR000500814.1)
2not providednot providednot provided

From Invitae, SCV000630295.3

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

Description

This sequence change replaces phenylalanine with cysteine at codon 252 of the ACADM protein (p.Phe252Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs780510026, ExAC 0.009%). This variant has been observed in several individuals with MCAD deficiency (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 226067). 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 and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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

From Knight Diagnostic Laboratories, Oregon Health and Sciences University, SCV001448920.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Natera, Inc., SCV001461469.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 11, 2021

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