NM_000018.4(ACADVL):c.1103A>C (p.Gln368Pro) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Sep 30, 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:: RCV000558671.16

Allele description [Variation Report for NM_000018.4(ACADVL):c.1103A>C (p.Gln368Pro)]

NM_000018.4(ACADVL):c.1103A>C (p.Gln368Pro)

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.1103A>C (p.Gln368Pro)

HGVS:

NC_000017.11:g.7223158A>C
NG_007975.1:g.8325A>C
NG_008391.2:g.1893T>G
NM_000018.4:c.1103A>CMANE SELECT
NM_001033859.3:c.1037A>C
NM_001270447.2:c.1172A>C
NM_001270448.2:c.875A>C
NP_000009.1:p.Gln368Pro
NP_001029031.1:p.Gln346Pro
NP_001257376.1:p.Gln391Pro
NP_001257376.1:p.Gln391Pro
NP_001257377.1:p.Gln292Pro
NP_001257377.1:p.Gln292Pro
NC_000017.10:g.7126477A>C
NM_000018.3:c.1103A>C
NM_001270447.1:c.1172A>C
NM_001270448.1:c.875A>C

Protein change:

Q292P

Links:

dbSNP: rs776063244

NCBI 1000 Genomes Browser:

rs776063244

Molecular consequence:

NM_000018.4:c.1103A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1037A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1172A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.875A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
Synonyms:: VLCAD deficiency
Identifiers:: MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

Recent activity

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ectonucleotide pyrophosphatase/phosphodiesterase family member 2 isoform X13 [Mu...
ectonucleotide pyrophosphatase/phosphodiesterase family member 2 isoform X13 [Mus musculus]
gi|1907110810|ref|XP_036015145.1|

Protein
Mus musculus ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2), transcr...
Mus musculus ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2), transcript variant 9, mRNA
gi|2293176090|ref|NM_001411655.1|

Nucleotide
PREDICTED: Canis lupus familiaris glutathione S-transferase omega 2 (GSTO2), tra...
PREDICTED: Canis lupus familiaris glutathione S-transferase omega 2 (GSTO2), transcript variant X3, mRNA
gi|1953038712|ref|XM_038578727.1|

Nucleotide
PREDICTED: Canis lupus familiaris glutathione S-transferase omega 2 (GSTO2), tra...
PREDICTED: Canis lupus familiaris glutathione S-transferase omega 2 (GSTO2), transcript variant X1, mRNA
gi|1953353888|ref|XM_038440496.1|

Nucleotide
translation elongation factor 1-alpha, partial [Paraphaeosphaeria arecacearum]
translation elongation factor 1-alpha, partial [Paraphaeosphaeria arecacearum]
gi|2735223332|gb|XBA91723.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000654918	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31031081, 28492532
SCV000891175	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 13, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26385305, 25741868
SCV001365226	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26385305, 25741868
SCV002060265	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 11, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26385305, 31031081 Citation Link,
SCV004215981	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
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

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

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ.

Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

PubMed [citation]

PMID:: 26385305
PMCID:: PMC4790081

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000654918.6

#	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 glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 368 of the ACADVL protein (p.Gln368Pro). This variant is present in population databases (rs776063244, gnomAD 0.0009%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 31031081). ClinVar contains an entry for this variant (Variation ID: 439360). 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. 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

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000891175.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

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

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001365226.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The NM_000018.3:c.1103A>C (NP_000009.1:p.Gln368Pro) [GRCH38: NC_000017.11:g.7223158A>C] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM1, PP3

#	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

From Myriad Genetics, Inc., SCV002060265.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

NM_000018.3(ACADVL):c.1103A>C(Q368P) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. Q368P has been observed in cases with relevant disease (PMID: 26385305, 31031081). Functional assessments of this variant are not available in the literature. Q368P has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1103A>C(Q368P) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	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 Baylor Genetics, SCV004215981.1

#	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

Last Updated: Sep 29, 2024

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