NM_000018.4(ACADVL):c.1238T>C (p.Ile413Thr) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 19, 2023
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:: RCV003474375.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.1238T>C (p.Ile413Thr)]

NM_000018.4(ACADVL):c.1238T>C (p.Ile413Thr)

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.1238T>C (p.Ile413Thr)

HGVS:

NC_000017.11:g.7223699T>C
NG_007975.1:g.8866T>C
NG_008391.2:g.1352A>G
NG_008391.3:g.1351A>G
NG_033038.1:g.15846A>G
NM_000018.4:c.1238T>CMANE SELECT
NM_001033859.3:c.1172T>C
NM_001270447.2:c.1307T>C
NM_001270448.2:c.1010T>C
NP_000009.1:p.Ile413Thr
NP_001029031.1:p.Ile391Thr
NP_001257376.1:p.Ile436Thr
NP_001257377.1:p.Ile337Thr
NC_000017.10:g.7127018T>C

Protein change:

I337T

Molecular consequence:

NM_000018.4:c.1238T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1172T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1307T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.1010T>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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actin-binding protein WASF2 isoform 1 [Homo sapiens]
actin-binding protein WASF2 isoform 1 [Homo sapiens]
gi|11386183|ref|NP_008921.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004210922	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004613719	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30950014, 35281659, 33150772, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004210922

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 19, 2023)

unknown

clinical testing

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

SCV004613719

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 8, 2023)

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
not provided	unknown	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

[Analysis of ACADVL gene variations among nine neonates with very long chain acyl-coA dehydrogenase deficiency].

Tong F, Chen T, Jiang P, Yang R, Zhao Z, Shu Q.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019 Apr 10;36(4):310-313. doi: 10.3760/cma.j.issn.1003-9406.2019.04.005. Chinese.

PubMed [citation]

PMID:: 30950014

See all PubMed Citations (5)

Details of each submission

From Baylor Genetics, SCV004210922.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004613719.1

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

Description

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 sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 413 of the ACADVL protein (p.Ile413Thr). This variant is present in population databases (rs775980475, gnomAD 0.0009%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 30950014, 35281659). Experimental studies have shown that this missense change affects ACADVL function (PMID: 33150772). 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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