NM_000016.6(ACADM):c.558T>A (p.Asn186Lys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 18, 2016
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000421950.7

Allele description [Variation Report for NM_000016.6(ACADM):c.558T>A (p.Asn186Lys)]

NM_000016.6(ACADM):c.558T>A (p.Asn186Lys)

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.558T>A (p.Asn186Lys)

HGVS:

NC_000001.11:g.75740069T>A
NG_007045.2:g.20712T>A
NM_000016.6:c.558T>AMANE SELECT
NM_001127328.3:c.570T>A
NM_001286042.2:c.450T>A
NM_001286043.2:c.657T>A
NM_001286044.2:c.-10T>A
NP_000007.1:p.Asn186Lys
NP_000007.1:p.Asn186Lys
NP_001120800.1:p.Asn190Lys
NP_001272971.1:p.Asn150Lys
NP_001272972.1:p.Asn219Lys
LRG_838t1:c.558T>A
LRG_838:g.20712T>A
LRG_838p1:p.Asn186Lys
NC_000001.10:g.76205754T>A
NM_000016.4:c.558T>A
NM_000016.5:c.558T>A

Protein change:

N150K

Links:

dbSNP: rs754359356

NCBI 1000 Genomes Browser:

rs754359356

Molecular consequence:

NM_001286044.2:c.-10T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000016.6:c.558T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127328.3:c.570T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286042.2:c.450T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001286043.2:c.657T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000231984	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Apr 20, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20434380, 22542437 Citation Link,
SCV000511931	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Feb 18, 2016)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000231984

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Apr 20, 2015)

germline

clinical testing

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

Citation Link,

SCV000511931

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Feb 18, 2016)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

MCAD deficiency in Denmark.

Andresen BS, Lund AM, Hougaard DM, Christensen E, Gahrn B, Christensen M, Bross P, Vested A, Simonsen H, Skogstrand K, Olpin S, Brandt NJ, Skovby F, Nørgaard-Pedersen B, Gregersen N.

Mol Genet Metab. 2012 Jun;106(2):175-88. doi: 10.1016/j.ymgme.2012.03.018. Epub 2012 Apr 4.

PubMed [citation]

PMID:: 22542437

Details of each submission

From Eurofins Ntd Llc (ga), SCV000231984.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV000511931.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

A N186K (c.558 T>A) variant that is likely pathogenic was identified in the ACADM gene. This variant has previously been reported in association with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (Andresen et al., 2012). Clinical studies of individuals identified by newborn screening and in vitro experiments indicate that N186K is a mild variant, associated with a milder biochemical phenotype (Andresen et al., 2012). Additionally, several in-silico splice prediction models predict that the c.558 T>A nucleotide substitution, responsible for N186K, creates a strong cryptic splice donor site, which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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