NM_000018.4(ACADVL):c.385GAG[1] (p.Glu130del) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Jan 17, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000001693.38

Allele description [Variation Report for NM_000018.4(ACADVL):c.385GAG[1] (p.Glu130del)]

NM_000018.4(ACADVL):c.385GAG[1] (p.Glu130del)

Gene:

ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.385GAG[1] (p.Glu130del)

Other names:

NM_000018.4(ACADVL):c.385GAG[1]

HGVS:

NC_000017.10:g.7124284_7124286del
NC_000017.11:g.7220966GAG[1]
NG_007975.1:g.6133GAG[1]
NG_007975.1:g.6136_6138del
NG_008391.2:g.4081TCC[1]
NM_000018.2:c.388_390del
NM_000018.4:c.385GAG[1]MANE SELECT
NM_001033859.3:c.319GAG[1]
NM_001270447.2:c.454GAG[1]
NM_001270448.2:c.157GAG[1]
NP_000009.1:p.Glu130del
NP_001029031.1:p.Glu108del
NP_001257376.1:p.Glu153del
NP_001257377.1:p.Glu54del
NC_000017.10:g.7124284_7124286del
NC_000017.10:g.7124285GAG[1]
NC_000017.10:g.7124288_7124290delGAG
NC_000017.11:g.7220966GAG[1]
NG_007975.1:g.6136_6138del
NM_000018.2:c.388_390delGAG
NM_000018.3:c.388_390del
NM_000018.3:c.388_390delGAG
NM_000018.4:c.388_390delMANE SELECT

Protein change:

E108del

Links:

OMIM: 609575.0006; dbSNP: rs387906251

NCBI 1000 Genomes Browser:

rs387906251

Molecular consequence:

NM_000018.4:c.385GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001033859.3:c.319GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270447.2:c.454GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270448.2:c.157GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021849	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1996)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000220634	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 25, 2014)	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 22847164, 8554073 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000773898	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10431122, 22847164, 27209629, 8554073, 28492532
SCV001160512	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Apr 19, 2019)	germline	clinical testing	Citation Link,
SCV001362322	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 26, 2019)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10431122, 26385305, 27209629, 26927351, 22847164, 8554073, 9599005 Citation Link,
SCV001364888	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8554073, 10431122, 25741868
SCV002088750	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 4, 2020)	germline	clinical testing
SCV002576771	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Jan 17, 2022)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002805584	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 31, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004214206	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 12, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

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 (9)

Details of each submission

From OMIM, SCV000021849.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with VLCAD deficiency (201475), Souri et al. (1996) identified a homozygous 3-bp deletion in the ACADVL gene (nucleotides 388-390), resulting in deletion of glu130 (E130X). In another patient, Souri et al. (1996) found the 3-bp deletion mutation in compound heterozygosity with the K382Q mutation (609575.0008).

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

From Counsyl, SCV000220634.2

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

#	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, SCV000773898.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant, c.388_390del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu130del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750138126, gnomAD 0.01%). This variant has been observed in individual(s) with very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) Deficiency (PMID: 8554073, 10431122, 22847164, 27209629). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1626). Studies have shown that this variant alters ACADVL gene expression (PMID: 8554073). For these reasons, this variant has been classified as 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160512.1

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

Description

The ACADVL c.388_390delGAG; p.Glu130del variant (rs387906251) is reported in the literature in the compound heterozygous state in multiple individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (Hahn 1999, Pena 2016, Siu 2012, Souri 1996). In vitro functional analyses demonstrate production of unstable transcripts and reduced enzyme activity (Souri 1996). This variant is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 1626), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single glutamic acid residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be pathogenic. References: Hahn SH et al. Very long chain acyl coenzyme A dehydrogenase deficiency in a 5-month-old Korean boy: identification of a novel mutation. J Pediatr. 1999 Aug;135(2 Pt 1):250-3. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. Siu WK et al. Molecular diagnosis for a fatal case of very long-chain acyl-CoA dehydrogenase deficiency in Hong Kong Chinese with a novel mutation: a preventable death by newborn screening. Diagn Mol Pathol. 2012 Sep;21(3):184-7. Souri M et al. Mutation analysis of very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. Am J Hum Genet. 1996 Jan;58(1):97-106.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362322.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: ACADVL c.388_390delGAG (p.Glu130del) results in an in-frame deletion that is predicted to remove one of two glutamate residues in codon 388-390. The variant allele was found at a frequency of 2e-05 in 251410 control chromosomes (gnomAD). The variant, c.388_390delGAG, has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Souri_1996, Hahn_1999, Siu_2012, Miller_2015, Pena_2016). These data indicate that the variant is very likely to be associated with disease. One paper reports this variant retain less than 10% of enzyme activity compared to WT (Souri_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as 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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364888.2

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

Description

The NM_000018.3:c.388_390delGAG (NP_000009.1:p.Glu130del) [GRCH38: NC_000017.11:g.7220969_7220971delGAG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8554073; 10431122. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

#	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 Natera, Inc., SCV002088750.1

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

#	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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002576771.2

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

Description

The c.385GAG[1] variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu130del) (PM4). This variant has been detected in at least five individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PMIDs 8554073, 10431122, 27209629,22847164). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those was confirmed in trans by parental testing (PM3_strong, PMID: 10431122). Several patients with this variant displayed VLCADD (PP4, PMIDs 8554073 , 10431122, 27209629, 22847164 ). Assays, including mRNA/protein expression (in CHO cells), and enzymatic activity demonstrate unstable protein products indicating that this variant impacts protein function (PMID: 8554073 )(PS3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM4, PM3_strong, PP4, PS3

#	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 Fulgent Genetics, Fulgent Genetics, SCV002805584.1

#	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 Baylor Genetics, SCV004214206.2

#	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: Nov 3, 2024

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