VCV000198379.21 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(2); Uncertain significance(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 198379 Accession: VCV000198379.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.1 1: 75740069 (GRCh38) [ NCBI UCSC ] 1: 76205754 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 21, 2016	Sep 16, 2024	Jan 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000016.6:c.558T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000007.1:p.Asn186Lys	missense
NM_001127328.3:c.570T>A	NP_001120800.1:p.Asn190Lys	missense
NM_001286042.2:c.450T>A	NP_001272971.1:p.Asn150Lys	missense
NM_001286043.2:c.657T>A	NP_001272972.1:p.Asn219Lys	missense
NM_001286044.2:c.-10T>A		5 prime UTR
NC_000001.11:g.75740069T>A
NC_000001.10:g.76205754T>A
NG_007045.2:g.20712T>A
LRG_838:g.20712T>A
LRG_838t1:c.558T>A	LRG_838p1:p.Asn186Lys

... more HGVS ... less HGVS

Protein change

N190K, N186K, N150K, N219K

Other names

Canonical SPDI

NC_000001.11:75740068:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA247000 dbSNP: rs754359356 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ACADM		-	-	GRCh38 GRCh37	892	924

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Medium-chain acyl-coenzyme A dehydrogenase deficiency	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 5, 2024	RCV000211498.19
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 17, 2023	RCV000421950.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Feb 20, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000268459.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016
Uncertain significance (Apr 20, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000231984.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 20434380‚ 22542437 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADM Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Nov 17, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000511931.4 First in ClinVar: Mar 08, 2017 Last updated: Sep 16, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22542437, 20434380, 27477829) (less)
Uncertain significance (May 12, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800531.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Publications: PubMed (2) PubMed: 20434380‚ 22542437
Pathogenic (Jul 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000940988.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 22542437‚ 20434380 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ACADM function (PMID: 22542437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADM protein function. ClinVar contains an entry for this variant (Variation ID: 198379). This missense change has been observed in individual(s) with Medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 20434380, 22542437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs754359356, gnomAD 0.002%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 186 of the ACADM protein (p.Asn186Lys). (less)
Pathogenic (Jan 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Medium-chain acyl-coenzyme A dehydrogenase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212269.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22542437, 20434380, 27477829)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ACADM function (PMID: 22542437). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADM protein function. ClinVar contains an entry for this variant (Variation ID: 198379). This missense change has been observed in individual(s) with Medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 20434380, 22542437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs754359356, gnomAD 0.002%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 186 of the ACADM protein (p.Asn186Lys).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
MCAD deficiency in Denmark.	Andresen BS	Molecular genetics and metabolism	2012	PMID: 22542437
Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.	Smith EH	Molecular genetics and metabolism	2010	PMID: 20434380
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ACADM	-	-	-	-

Text-mined citations for rs754359356 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs754359356 ...