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

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 9, 2020)

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:
RCV000211454.5

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_000016.5:c.347G>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
  • 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_000016.5:c.347G>A - missense variant - [Sequence Ontology: SO:0001583]
  • 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000268452ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Feb 20, 2015)
germlineclinical testing

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

SCV000792310Counsylcriteria provided, single submitter
Likely pathogenic
(Oct 4, 2017)
unknownclinical testing

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

Citation Link,

SCV000933584Invitaecriteria provided, single submitter
Pathogenic
(Sep 9, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?

Andresen BS, Bross P, Udvari S, Kirk J, Gray G, Kmoch S, Chamoles N, Knudsen I, Winter V, Wilcken B, Yokota I, Hart K, Packman S, Harpey JP, Saudubray JM, Hale DE, Bolund L, Kølvraa S, Gregersen N.

Hum Mol Genet. 1997 May;6(5):695-707.

PubMed [citation]
PMID:
9158144
See all PubMed Citations (6)

Details of each submission

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

#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 Counsyl, SCV000792310.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000933584.3

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

Description

This sequence change replaces cysteine with tyrosine at codon 116 of the ACADM protein (p.Cys116Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ACADM variant in individuals affected with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 9158144, 20567907, 19649258, 29285339). This variant is also known as C91Y in the literature. ClinVar contains an entry for this variant (Variation ID: 226068). 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

Last Updated: Nov 27, 2021

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