NM_000018.4(ACADVL):c.514C>T (p.Leu172Phe) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 2, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003864987.1

Allele description [Variation Report for NM_000018.4(ACADVL):c.514C>T (p.Leu172Phe)]

NM_000018.4(ACADVL):c.514C>T (p.Leu172Phe)

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.514C>T (p.Leu172Phe)

HGVS:

NC_000017.11:g.7221574C>T
NG_007975.1:g.6741C>T
NG_008391.2:g.3477G>A
NG_008391.3:g.3476G>A
NM_000018.4:c.514C>TMANE SELECT
NM_001033859.3:c.448C>T
NM_001270447.2:c.583C>T
NM_001270448.2:c.286C>T
NP_000009.1:p.Leu172Phe
NP_001029031.1:p.Leu150Phe
NP_001257376.1:p.Leu195Phe
NP_001257377.1:p.Leu96Phe
NC_000017.10:g.7124893C>T

Protein change:

L150F

Molecular consequence:

NM_000018.4:c.514C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.448C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.583C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.286C>T - 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
SCV004672965	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30194637, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004672965

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 2, 2024)

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

The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD).

Hesse J, Braun C, Behringer S, Matysiak U, Spiekerkoetter U, Tucci S.

J Inherit Metab Dis. 2018 Nov;41(6):1169-1178. doi: 10.1007/s10545-018-0245-5. Epub 2018 Sep 7.

PubMed [citation]

PMID:: 30194637

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

Details of each submission

From Invitae, SCV004672965.1

#	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 phenylalanine, which is neutral and non-polar, at codon 172 of the ACADVL protein (p.Leu172Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. 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 with a positive predictive value of 95%. This variant disrupts the p.Leu172 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30194637). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Mar 5, 2024

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