NM_000018.4(ACADVL):c.1700G>A (p.Arg567Gln) AND Very long chain acyl-CoA dehydrogenase deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 11, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000813614.7

Allele description

NM_000018.4(ACADVL):c.1700G>A (p.Arg567Gln)

Gene:

ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1700G>A (p.Arg567Gln)

HGVS:

NC_000017.11:g.7224663G>A
NG_007975.1:g.9830G>A
NG_008391.2:g.388C>T
NG_033038.1:g.14882C>T
NM_000018.4:c.1700G>AMANE SELECT
NM_001033859.2:c.1634G>A
NM_001270447.1:c.1769G>A
NM_001270448.1:c.1472G>A
NP_000009.1:p.Arg567Gln
NP_000009.1:p.Arg567Gln
NP_001029031.1:p.Arg545Gln
NP_001257376.1:p.Arg590Gln
NP_001257377.1:p.Arg491Gln
NC_000017.10:g.7127982G>A
NM_000018.3:c.1700G>A

Protein change:

R491Q

Links:

dbSNP: rs398123084

NCBI 1000 Genomes Browser:

rs398123084

Molecular consequence:

NM_000018.4:c.1700G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.2:c.1634G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.1:c.1769G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.1:c.1472G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
Synonyms:: VLCAD deficiency
Identifiers:: MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000953981	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 24, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23480858, 28492532
SCV001140233	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001158615	ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Mar 11, 2020)	germline	clinical testing	Citation Link,
SCV001364939	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23480858, 25741868
SCV001522462	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 30, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency.

Schiff M, Mohsen AW, Karunanidhi A, McCracken E, Yeasted R, Vockley J.

Mol Genet Metab. 2013 May;109(1):21-7. doi: 10.1016/j.ymgme.2013.02.002. Epub 2013 Feb 13.

PubMed [citation]

PMID:: 23480858
PMCID:: PMC3628282

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000953981.2

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

Description

This sequence change replaces arginine with glutamine at codon 567 of the ACADVL protein (p.Arg567Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs398123084, ExAC 0.09%). This variant has been observed in combination with another ACADVL variant in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23480858, Invitae). ClinVar contains an entry for this variant (Variation ID: 92278). Experimental studies have shown that this missense change abrogates ACADVL enzyme activity (PMID: 23480858). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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		not provided	not provided	not provided	not provided

From Mendelics, SCV001140233.1

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

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001158615.2

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

Description

The ACADVL c.1700G>A; p.Arg567Gln variant (rs398123084) is reported in the literature in an individual with elevated acylcarnitine levels (Schiff 2013). In testing performed at ARUP Laboratories, this variant has also been observed in at least one individual with an abnormal newborn screen for VLCAD deficiency that also carried an additional pathogenic variant. The p.Arg567Gln variant is reported in ClinVar (Variation ID: 92278), and it is found in the general population with an overall allele frequency of 0.01% (23/210246 alleles) in the Genome Aggregation Database. The arginine at codon 567 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In a biochemical VLCAD activity assay, the p.Arg567Gln variant protein exhibits 21% of wildtype activity (Schiff 2013). While this reduced activity may be attributable to reduced enzyme synthesis or stability by an uncertain mechanism, the decreased activity in the biochemical assay is consistent with reduced VLCAD activity measured in patient fibroblasts (Schiff 2013). Based on available information, the p.Arg567Gln variant is considered to be likely pathogenic. References: Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7.

#	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		not provided	not provided	not provided	not provided

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364939.2

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

Description

The NM_000018.3:c.1700G>A (NP_000009.1:p.Arg567Gln) [GRCH38: NC_000017.11:g.7224663G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 23480858. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

#	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		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001522462.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: May 1, 2021

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