NM_000018.4(ACADVL):c.481G>T (p.Ala161Ser) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 6, 2023
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:: RCV003600504.2

Allele description [Variation Report for NM_000018.4(ACADVL):c.481G>T (p.Ala161Ser)]

NM_000018.4(ACADVL):c.481G>T (p.Ala161Ser)

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.481G>T (p.Ala161Ser)

HGVS:

NC_000017.11:g.7221541G>T
NG_007975.1:g.6708G>T
NG_008391.2:g.3510C>A
NG_008391.3:g.3509C>A
NM_000018.4:c.481G>TMANE SELECT
NM_001033859.3:c.415G>T
NM_001270447.2:c.550G>T
NM_001270448.2:c.253G>T
NP_000009.1:p.Ala161Ser
NP_001029031.1:p.Ala139Ser
NP_001257376.1:p.Ala184Ser
NP_001257377.1:p.Ala85Ser
NC_000017.10:g.7124860G>T

Protein change:

A139S

Molecular consequence:

NM_000018.4:c.481G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.415G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.550G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.253G>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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SLC5A1 [Cebus imitator]
SLC5A1 [Cebus imitator]
Gene ID:108283263

Gene
COLGALT1 [Cebus imitator]
COLGALT1 [Cebus imitator]
Gene ID:108284524

Gene
Pain Measurement
Pain Measurement
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004374192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16488171, 16950999, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004374192

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 6, 2023)

germline

clinical testing

PubMed (3)
[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

VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis.

Boneh A, Andresen BS, Gregersen N, Ibrahim M, Tzanakos N, Peters H, Yaplito-Lee J, Pitt JJ.

Mol Genet Metab. 2006 Jun;88(2):166-70. Epub 2006 Feb 20.

PubMed [citation]

PMID:: 16488171

Neonatal screening for very long-chain acyl-coA dehydrogenase deficiency: enzymatic and molecular evaluation of neonates with elevated C14:1-carnitine levels.

Liebig M, Schymik I, Mueller M, Wendel U, Mayatepek E, Ruiter J, Strauss AW, Wanders RJ, Spiekerkoetter U.

Pediatrics. 2006 Sep;118(3):1065-9.

PubMed [citation]

PMID:: 16950999

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004374192.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the ACADVL protein (p.Ala161Ser). This variant is present in population databases (rs375284481, gnomAD 0.008%). 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.Ala161 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16488171, 16950999; Invitae). 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: Sep 29, 2024

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