NM_000018.4(ACADVL):c.739A>G (p.Lys247Glu) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 19, 2023
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:: RCV000668561.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.739A>G (p.Lys247Glu)]

NM_000018.4(ACADVL):c.739A>G (p.Lys247Glu)

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.739A>G (p.Lys247Glu)

HGVS:

NC_000017.11:g.7222068A>G
NG_007975.1:g.7235A>G
NG_008391.2:g.2983T>C
NM_000018.4:c.739A>GMANE SELECT
NM_001033859.3:c.673A>G
NM_001270447.2:c.808A>G
NM_001270448.2:c.511A>G
NP_000009.1:p.Lys247Glu
NP_001029031.1:p.Lys225Glu
NP_001257376.1:p.Lys270Glu
NP_001257377.1:p.Lys171Glu
NC_000017.10:g.7125387A>G
NM_000018.3:c.739A>G

Protein change:

K171E

Links:

dbSNP: rs387906253

NCBI 1000 Genomes Browser:

rs387906253

Molecular consequence:

NM_000018.4:c.739A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.673A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.808A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.511A>G - 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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Homo sapiens killer cell lectin-like receptor subfamily C, member 4 (KLRC4), mRN...
Homo sapiens killer cell lectin-like receptor subfamily C, member 4 (KLRC4), mRNA
gi|7710123|ref|NM_013431.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000793183	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jul 31, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004297751	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10790204, 10077518, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000793183

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Jul 31, 2017)

unknown

clinical testing

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

Citation Link,

SCV004297751

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 19, 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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of very long chain acyl-CoA dehydrogenase deficiency in three Israeli patients: identification of a complex mutant allele with P65L and K247Q mutations, the former being an exonic mutation causing exon 3 skipping.

Watanabe H, Orii KE, Fukao T, Song XQ, Aoyama T, IJlst L, Ruiter J, Wanders RJ, Kondo N.

Hum Mutat. 2000;15(5):430-8.

PubMed [citation]

PMID:: 10790204

Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death.

Mathur A, Sims HF, Gopalakrishnan D, Gibson B, Rinaldo P, Vockley J, Hug G, Strauss AW.

Circulation. 1999 Mar 16;99(10):1337-43.

PubMed [citation]

PMID:: 10077518

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000793183.1

#	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, SCV004297751.1

#	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 lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 247 of the ACADVL protein (p.Lys247Glu). This variant is not present in population databases (gnomAD no frequency). 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.Lys247 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10077518, 10790204). 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. ClinVar contains an entry for this variant (Variation ID: 553167). This variant is also known as K207E. This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 10077518).

#	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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