NM_000016.6(ACADM):c.1257C>A (p.Tyr419Ter) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Clinical significance:Uncertain significance (Last evaluated: Sep 12, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000633659.5

Allele description [Variation Report for NM_000016.6(ACADM):c.1257C>A (p.Tyr419Ter)]

NM_000016.6(ACADM):c.1257C>A (p.Tyr419Ter)

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.1257C>A (p.Tyr419Ter)
HGVS:
  • NC_000001.11:g.75762754C>A
  • NG_007045.2:g.43397C>A
  • NM_000016.6:c.1257C>AMANE SELECT
  • NM_001127328.3:c.1269C>A
  • NM_001286042.2:c.1149C>A
  • NM_001286043.2:c.1356C>A
  • NM_001286044.2:c.690C>A
  • NP_000007.1:p.Tyr419Ter
  • NP_000007.1:p.Tyr419Ter
  • NP_001120800.1:p.Tyr423Ter
  • NP_001272971.1:p.Tyr383Ter
  • NP_001272972.1:p.Tyr452Ter
  • NP_001272973.1:p.Tyr230Ter
  • LRG_838t1:c.1257C>A
  • LRG_838:g.43397C>A
  • LRG_838p1:p.Tyr419Ter
  • NC_000001.10:g.76228439C>A
  • NM_000016.4:c.1257C>A
  • NM_000016.5:c.1257C>A
Protein change:
Y230*
Links:
dbSNP: rs753928772
NCBI 1000 Genomes Browser:
rs753928772
Molecular consequence:
  • NM_000016.6:c.1257C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001127328.3:c.1269C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001286042.2:c.1149C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001286043.2:c.1356C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001286044.2:c.690C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000754916Invitaecriteria provided, single submitter
Uncertain significance
(Sep 12, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000798782Counsylno assertion criteria providedLikely pathogenic
(Dec 26, 2018)
unknownclinical testing

PubMed (2)
[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

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

Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.

Arnold GL, Saavedra-Matiz CA, Galvin-Parton PA, Erbe R, Devincentis E, Kronn D, Mofidi S, Wasserstein M, Pellegrino JE, Levy PA, Adams DJ, Nichols M, Caggana M.

Mol Genet Metab. 2010 Mar;99(3):263-8. doi: 10.1016/j.ymgme.2009.10.188. Epub 2009 Nov 1.

PubMed [citation]
PMID:
20036593
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000754916.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change results in a premature translational stop signal in the ACADM gene (p.Tyr419*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 3 amino acids of the ACADM protein. This variant is present in population databases (rs753928772, ExAC 0.003%). This variant has not been reported in the literature in individuals with ACADM-related disease. ClinVar contains an entry for this variant (Variation ID: 488675). A different variant (c.1257C>G) giving rise to the same protein effect (p.Tyr419*) has been reported in an individual affected with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 24966162). Experimental studies showed that c.1257C>G did not lead to NMD but does impair ACADM enzymatic activity. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Counsyl, SCV000798782.2

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

Last Updated: Dec 4, 2021

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