NM_000016.6(ACADM):c.199T>C (p.Tyr67His) AND Medium-chain acyl-coenzyme A dehydrogenase deficiency

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

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000003780.15

Allele description [Variation Report for NM_000016.6(ACADM):c.199T>C (p.Tyr67His)]

NM_000016.6(ACADM):c.199T>C (p.Tyr67His)

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.199T>C (p.Tyr67His)
Other names:
Y42H; p.Y67H:TAT>CAT; MC Y67h
HGVS:
  • NC_000001.11:g.75732724T>C
  • NG_007045.2:g.13367T>C
  • NM_000016.5:c.199T>C
  • NM_000016.6:c.199T>CMANE SELECT
  • NM_001127328.2:c.211T>C
  • NM_001286042.1:c.91T>C
  • NM_001286043.1:c.199T>C
  • NM_001286044.1:c.-187T>C
  • NP_000007.1:p.Tyr67His
  • NP_000007.1:p.Tyr67His
  • NP_001120800.1:p.Tyr71His
  • NP_001272971.1:p.Tyr31His
  • NP_001272972.1:p.Tyr67His
  • LRG_838t1:c.199T>C
  • LRG_838:g.13367T>C
  • LRG_838p1:p.Tyr67His
  • NC_000001.10:g.76198409T>C
  • NM_000016.4:c.199T>C
  • NM_001127328.1:c.211T>C
  • P11310:p.Tyr67His
Nucleotide change:
199T>C
Protein change:
Y31H; TYR42HIS
Links:
UniProtKB: P11310#VAR_013698; OMIM: 607008.0011; dbSNP: rs121434280
NCBI 1000 Genomes Browser:
rs121434280
Molecular consequence:
  • NM_001286044.1:c.-187T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000016.5:c.199T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000016.6:c.199T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127328.2:c.211T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286042.1:c.91T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001286043.1:c.199T>C - 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
SCV000023945OMIMno assertion criteria providedPathogenic
(Mar 1, 2008)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

SCV000056311ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Aug 17, 2020)
germlineclinical testing

Citation Link,

SCV000630280Invitaecriteria provided, single submitter
Pathogenic
(Oct 26, 2020)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV000693956Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Dec 15, 2016)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000711420Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Mar 31, 2017)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001193986Myriad Women's Health, Inc.criteria provided, single submitter
Pathogenic
(Dec 20, 2019)
unknownclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV001251466UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill - NSIGHT-NC NEXUScriteria provided, single submitter
Pathogenicgermlineresearch

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 providedgermlineyes1not providednot providednot providednot providedresearch
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing

Citations

PubMed

Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population.

Nichols MJ, Saavedra-Matiz CA, Pass KA, Caggana M.

Am J Med Genet A. 2008 Mar 1;146A(5):610-9. doi: 10.1002/ajmg.a.32192.

PubMed [citation]
PMID:
18241067

Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.

Waddell L, Wiley V, Carpenter K, Bennetts B, Angel L, Andresen BS, Wilcken B.

Mol Genet Metab. 2006 Jan;87(1):32-9. Epub 2005 Nov 15.

PubMed [citation]
PMID:
16291504
See all PubMed Citations (24)

Details of each submission

From OMIM, SCV000023945.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

This mutation has also been called TYR67HIS (Y67H).

In 7 newborns with MCAD deficiency (201450), Andresen et al. (2001) identified a new mutation, a 199T-C change resulting in a tyr42-to-his (Y42H) substitution. Although this mutation had never been observed in patients with clinically manifest disease, it was present in a large proportion of the acylcarnitine-positive samples. The Y42H mutation was found to have a carrier frequency of 1 in 500 in the general population, and overexpression experiments showed that it is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. In all cases in which haplotyping was performed, the 199T-C mutation was found on the same haplotype, indicating a common origin of the mutant allele.

In 2 patients with MCAD deficiency, Zschocke et al. (2001) found the same mutation, which they called a tyr67-to-his mutation. The mutation was found in compound heterozygosity with the K329E mutation (607008.0001) in both patients.

By in vitro studies, O'Reilly et al. (2004) determined that the Y42H mutation compromised enzyme activity to only a minor degree. Substrate binding, interaction with the natural electron acceptor, and binding of the prosthetic group FAD were only slightly affected by the Y42H mutation. However, thermostability of the Y42H variant was decreased compared to wildtype protein but not to the same degree as that of the K304E variant. The findings suggested that Y42H is a temperature-sensitive mutation, which is mild at low temperatures, but may have deleterious effects at increased temperatures.

Nichols et al. (2008) found that Y42H was the second (7.5%) most common ACADM mutation in New York state over an 18-month period of newborn screening. K304E was most common, accounting for 47.5% of mutant ACADM alleles.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000056311.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ACADM c.199T>C; p.Tyr67His variant (rs121434280), also known as Y42H, has been identified through newborn screening and results in an abnormal acylcarnitine profile when paired with a second ACADM pathogenic variant on the opposite allele (Maier 2009, O'Reilly 2004, Zschocke 2001). This variant is also reported as pathogenic by several laboratories in ClinVar (Variation ID: 3597). It is found in the general population with an overall allele frequency of 0.05% (140/282696 alleles) in the Genome Aggregation Database. Functional analyses demonstrate that this variant results in a temperature-sensitive enzyme with partial activity (Jank 2014, Maier 2009, O'Reilly 2004). Based on available information, this variant is considered to be pathogenic. REFERENCES Jank J et al. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One. 2014 Apr 9;9(4):e93852. Maier EM et al. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum. Mol. Genet. 2009; 18(9):1612-23. O'Reilly L et al. The Y42H mutation in medium-chain acyl-CoA dehydrogenase, which is prevalent in babies identified by MS/MS-based newborn screening, is temperature sensitive. Eur. J. Biochem. 2004; 271(20):4053-63. Zschocke J et al. Molecular and functional characterisation of mild MCAD deficiency. Hum. Genet. 2001; 108(5):404-8.

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

From Invitae, SCV000630280.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces tyrosine with histidine at codon 67 of the ACADM protein (p.Tyr67His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs121434280, ExAC 0.1%). This variant is known as a prevalent ACADM mutation identified in individuals positive for newborn screening (PMID: 15479234). This variant has mostly been found in individuals with biochemically confirmed MCAD deficiency as compound heterozygous with the pathogenic variant c.985A>G (p.Lys329Glu) (PMID: 16291504, 22166308, 18188679, 20434380, 20036593). It has also been observed as compound heterozygous with other severe ACADM mutations in individuals affected with neonatal decompensation with hypoglycemia (PMID: 22848008, 25940036). This variant is also known as p.Y42H in the literature. ClinVar contains an entry for this variant (Variation ID: 3597). Experimental studies have consistently shown that this variant results in a temperature-sensitive enzyme with partial activity (PMID: 15479234, 19224950, 24718418). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000693956.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: The ACADM c.199T>C (p.Tyr67His) variant located in the Acyl-CoA dehydrogenase/oxidase, N-terminal and middle domain causes a missense change involving a conserved nucleotide that 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predict a benign outcome. The variant of interest was observed in controls with an allele frequency of 74/121100 (1/1636), which does not exceed the estimated maximal expected allele frequency for a pathogenic ACADM variant of 1/184. The variant of interest has been reported in multiple affected individuals as compound heterozygous, which have been implicated to have mild phenotypes, to the point where multiple authors indicate individuals with this variant do not present clinically. In addition, multiple functional studies have been performed and show the variant has a mild affect on wild type functionality. In addition, multiple clinical diagnostic laboratories/databases cite variant as "pathogenic." Therefore, taking all available information into consideration, the variant of interest has been classified as "pathogenic" for a mild MCAD phenotype.

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

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000711420.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (11)

Description

The p.Tyr71His variant in ACADM (NM_001127328.1 c.211T>C; also referred to as c. 199Y>C, T42H, and T67H) has been reported in > 15 compound heterozygous individu als with mild medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Zschocke 20 01, Touw 2013, and Gramer 2015), and segregated in 1 sibling in 1 family (Touw 2 013). This variant has also been reported in ClinVar (Variation ID#3597). This v ariant has been identified in 0.10% (69/66,614) of European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs12143 4280). Although this variant has been seen in the general population, its freque ncy is low enough to be consistent with a recessive carrier frequency, particula rly with one presenting with a mild phenotype. In vitro functional studies provi de some evidence that the p.Tyr71 variant may modestly impact protein function ( O'Reilly 2004, Maier 2009, Koster 2014, Jank 2014, and Hara 2016). However, thes e assays show a decreased, but not eliminated, residual activity. It is unclear how this mild biochemical reduction may lead to a clinical phenotype. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Tyr71His variant is likely pathogenic in an autosomal recessive m anner for mild MCAD deficiency.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Myriad Women's Health, Inc., SCV001193986.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

NM_000016.4(ACADM):c.199T>C(Y67H) is classified as pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency and is associated with a mild form of this disease. Sources cited for classification include the following: PMIDs: 15832312, 20434380, 11409868, 19224950, 23028790, 23509891, and 24718418. Classification of NM_000016.4(ACADM):c.199T>C(Y67H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

From UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251466.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (5)

Description

The ACADM c.199T>C (p.Y67H) missense variant has been previously reported as pathogenic for medium-chain acyl-coA dehydrogenase deficiency in compound heterozygous individuals with a second, more severe ACADM variant. This variant is also referred to as Y42H (PMID: 11409868; 25940036; 11349232).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jul 10, 2021

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