NM_000018.4(ACADVL):c.495G>T (p.Glu165Asp) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 8, 2022
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:: RCV001372480.15

Allele description [Variation Report for NM_000018.4(ACADVL):c.495G>T (p.Glu165Asp)]

NM_000018.4(ACADVL):c.495G>T (p.Glu165Asp)

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.495G>T (p.Glu165Asp)

HGVS:

NC_000017.11:g.7221555G>T
NG_007975.1:g.6722G>T
NG_008391.2:g.3496C>A
NM_000018.4:c.495G>TMANE SELECT
NM_001033859.3:c.429G>T
NM_001270447.2:c.564G>T
NM_001270448.2:c.267G>T
NP_000009.1:p.Glu165Asp
NP_000009.1:p.Glu165Asp
NP_000009.1:p.Glu165Asp
NP_001029031.1:p.Glu143Asp
NP_001257376.1:p.Glu188Asp
NP_001257377.1:p.Glu89Asp
NP_001257377.1:p.Glu89Asp
NC_000017.10:g.7124874G>T
NM_000018.3:c.495G>T
NM_001270448.1:c.267G>T

Protein change:

E143D

Links:

dbSNP: rs370169077

NCBI 1000 Genomes Browser:

rs370169077

Molecular consequence:

NM_000018.4:c.495G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.429G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.564G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.267G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

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gigaxonin isoform 2 [Homo sapiens]
gigaxonin isoform 2 [Homo sapiens]
gi|1797095167|ref|NP_001364415.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001569147	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002088752	Natera, Inc.	no assertion criteria provided	Uncertain significance (Feb 27, 2020)	germline	clinical testing
SCV004704601	Clinical Genomics Laboratory, Stanford Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001569147

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 8, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002088752

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Feb 27, 2020)

germline

clinical testing

SCV004704601

Clinical Genomics Laboratory, Stanford Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 27, 2021)

germline

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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001569147.2

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 165 of the ACADVL protein (p.Glu165Asp). This variant is present in population databases (rs370169077, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. ClinVar contains an entry for this variant (Variation ID: 92285). 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 ACADVL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Natera, Inc., SCV002088752.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics Laboratory, Stanford Medicine, SCV004704601.1

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

Description

The p.Glu165Asp variant in the ACADVL gene has not been previously reported in association with disease. This variant has been identified in 11/113,750 European (non-Finnish) chromosomes (11/251,472 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational tools predict that the p.Glu165Asp variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Glu165Asp variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP3]

#	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		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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