NM_000018.4(ACADVL):c.665G>C (p.Gly222Ala) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 2022
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:: RCV003872432.2

Allele description [Variation Report for NM_000018.4(ACADVL):c.665G>C (p.Gly222Ala)]

NM_000018.4(ACADVL):c.665G>C (p.Gly222Ala)

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.665G>C (p.Gly222Ala)

HGVS:

NC_000017.11:g.7221994G>C
NG_007975.1:g.7161G>C
NG_008391.2:g.3057C>G
NG_008391.3:g.3056C>G
NM_000018.4:c.665G>CMANE SELECT
NM_001033859.3:c.599G>C
NM_001270447.2:c.734G>C
NM_001270448.2:c.437G>C
NP_000009.1:p.Gly222Ala
NP_001029031.1:p.Gly200Ala
NP_001257376.1:p.Gly245Ala
NP_001257377.1:p.Gly146Ala
NC_000017.10:g.7125313G>C

Protein change:

G146A

Molecular consequence:

NM_000018.4:c.665G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.599G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.734G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.437G>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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RecName: Full=Solute carrier family 22 member 17; AltName: Full=24p3 receptor; S...
RecName: Full=Solute carrier family 22 member 17; AltName: Full=24p3 receptor; Short=24p3R; AltName: Full=Brain-type organic cation transporter; AltName: Full=Lipocalin-2 receptor; AltName: Full=Neutrophil gelatinase-associated lipocalin receptor; Short=NgalR
gi|27805426|sp|Q8WUG5.1|S22AH_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004686469	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20060901, 25652019, 26182500, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004686469

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (4)
[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

Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches.

Gobin-Limballe S, McAndrew RP, Djouadi F, Kim JJ, Bastin J.

Biochim Biophys Acta. 2010 May;1802(5):478-84. doi: 10.1016/j.bbadis.2010.01.001. Epub 2010 Jan 12.

PubMed [citation]

PMID:: 20060901
PMCID:: PMC3401415

Very long-chain acyl-coenzyme A dehydrogenase deficiency in Chinese patients: eight case reports, including one case of prenatal diagnosis.

Li X, Ding Y, Ma Y, Liu Y, Wang Q, Song J, Yang Y.

Eur J Med Genet. 2015 Mar;58(3):134-9. doi: 10.1016/j.ejmg.2015.01.005. Epub 2015 Jan 31.

PubMed [citation]

PMID:: 25652019

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004686469.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. This variant disrupts the p.Gly222 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20060901, 25652019, 26182500). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 222 of the ACADVL protein (p.Gly222Ala).

#	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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