NM_000016.6(ACADM):c.1207A>G (p.Thr403Ala) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 26, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000670850.3

Allele description [Variation Report for NM_000016.6(ACADM):c.1207A>G (p.Thr403Ala)]

NM_000016.6(ACADM):c.1207A>G (p.Thr403Ala)

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.1207A>G (p.Thr403Ala)
HGVS:
  • NC_000001.11:g.75762704A>G
  • NG_007045.2:g.43347A>G
  • NM_000016.5:c.1207A>G
  • NM_000016.6:c.1207A>GMANE SELECT
  • NM_001127328.3:c.1219A>G
  • NM_001286042.2:c.1099A>G
  • NM_001286043.2:c.1306A>G
  • NM_001286044.2:c.640A>G
  • NP_000007.1:p.Thr403Ala
  • NP_000007.1:p.Thr403Ala
  • NP_001120800.1:p.Thr407Ala
  • NP_001272971.1:p.Thr367Ala
  • NP_001272972.1:p.Thr436Ala
  • NP_001272973.1:p.Thr214Ala
  • LRG_838t1:c.1207A>G
  • LRG_838:g.43347A>G
  • LRG_838p1:p.Thr403Ala
  • NC_000001.10:g.76228389A>G
  • NM_000016.4:c.1207A>G
Protein change:
T214A
Links:
dbSNP: rs1462472677
NCBI 1000 Genomes Browser:
rs1462472677
Molecular consequence:
  • NM_000016.5:c.1207A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000016.6:c.1207A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127328.3:c.1219A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286042.2:c.1099A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286043.2:c.1306A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286044.2:c.640A>G - 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
SCV000795761Counsylcriteria provided, single submitter
Likely pathogenic
(Nov 21, 2017)
unknownclinical testing

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

Citation Link,

SCV001409308Invitaecriteria provided, single submitter
Pathogenic
(Aug 26, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing.

Narravula A, Garber KB, Askree SH, Hegde M, Hall PL.

Genet Med. 2017 Jan;19(1):77-82. doi: 10.1038/gim.2016.67. Epub 2016 Jun 16.

PubMed [citation]
PMID:
27308838

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 (3)

Details of each submission

From Counsyl, SCV000795761.1

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

From Invitae, SCV001409308.2

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

Description

This sequence change replaces threonine with alanine at codon 403 of the ACADM protein (p.Thr403Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 20434380, 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: 555100). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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: Oct 30, 2021

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