NM_000018.4(ACADVL):c.533T>C (p.Leu178Pro) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 13, 2022
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:: RCV001200737.13

Allele description [Variation Report for NM_000018.4(ACADVL):c.533T>C (p.Leu178Pro)]

NM_000018.4(ACADVL):c.533T>C (p.Leu178Pro)

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.533T>C (p.Leu178Pro)

HGVS:

NC_000017.11:g.7221593T>C
NG_007975.1:g.6760T>C
NG_008391.2:g.3458A>G
NM_000018.4:c.533T>CMANE SELECT
NM_001033859.3:c.467T>C
NM_001270447.2:c.602T>C
NM_001270448.2:c.305T>C
NP_000009.1:p.Leu178Pro
NP_001029031.1:p.Leu156Pro
NP_001257376.1:p.Leu201Pro
NP_001257377.1:p.Leu102Pro
NC_000017.10:g.7124912T>C
NM_000018.2:c.533T>C
NM_000018.3:c.533T>C

Protein change:

L102P

Links:

dbSNP: rs1131691808

NCBI 1000 Genomes Browser:

rs1131691808

Molecular consequence:

NM_000018.4:c.533T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.467T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.602T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.305T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
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
SCV001365030	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001473227	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Sep 18, 2019)	germline	clinical testing	Citation Link,
SCV002143288	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21932095, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001365030

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 1, 2019)

germline

clinical testing

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

SCV001473227

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Sep 18, 2019)

germline

clinical testing

Citation Link,

SCV002143288

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 13, 2022)

germline

clinical testing

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

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

Citations

PubMed

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

VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment.

Hoffmann L, Haussmann U, Mueller M, Spiekerkoetter U.

J Inherit Metab Dis. 2012 Mar;35(2):269-77. doi: 10.1007/s10545-011-9391-8. Epub 2011 Sep 20.

PubMed [citation]

PMID:: 21932095

See all PubMed Citations (3)

Details of each submission

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001365030.2

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

Description

The NM_000018.3:c.533T>C (NP_000009.1:p.Leu178Pro) [GRCH38: NC_000017.11:g.7221593T>C] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM1, PM3, PP3, PP4

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473227.1

#	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.533T>C; p.Leu178Pro variant (rs1131691808), also published as p.Leu138Pro, is reported in the literature in an individual with a positive newborn screen for VLCAD deficiency and a residual enzyme activity measured at 33% of normal (Hoffman 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 178 is moderately conserved, it occurs in the substrate binding cavity (Hoffman 2012), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002143288.2

#	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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 178 of the ACADVL protein (p.Leu178Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency although a second variant was not observed (PMID: 21932095). ClinVar contains an entry for this variant (Variation ID: 430156). 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

Last Updated: Sep 29, 2024

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