NM_000018.4(ACADVL):c.1153C>T (p.Arg385Trp) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (8 submissions)
Last evaluated:: Mar 19, 2024
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:: RCV000668844.23

Allele description [Variation Report for NM_000018.4(ACADVL):c.1153C>T (p.Arg385Trp)]

NM_000018.4(ACADVL):c.1153C>T (p.Arg385Trp)

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.1153C>T (p.Arg385Trp)

HGVS:

NC_000017.11:g.7223208C>T
NG_007975.1:g.8375C>T
NG_008391.2:g.1843G>A
NM_000018.4:c.1153C>TMANE SELECT
NM_001033859.3:c.1087C>T
NM_001270447.2:c.1222C>T
NM_001270448.2:c.925C>T
NP_000009.1:p.Arg385Trp
NP_001029031.1:p.Arg363Trp
NP_001257376.1:p.Arg408Trp
NP_001257377.1:p.Arg309Trp
NC_000017.10:g.7126527C>T
NM_000018.2:c.1153C>T
NM_000018.3:c.1153C>T

Protein change:

R309W

Links:

dbSNP: rs745832866

NCBI 1000 Genomes Browser:

rs745832866

Molecular consequence:

NM_000018.4:c.1153C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1087C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1222C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.925C>T - 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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curcumin 4,4'-diacetate [Supplementary Concept]
curcumin 4,4'-diacetate [Supplementary Concept]
Date introduced: December 14, 1993<br/>

MeSH
Curcumin diacetate (1)
MeSH
HIT family protein [Mycobacterium tuberculosis]
HIT family protein [Mycobacterium tuberculosis]
gi|2742942701|ref|WP_349438761.1|

Protein
LLM class F420-dependent oxidoreductase [Mycobacterium tuberculosis]
LLM class F420-dependent oxidoreductase [Mycobacterium tuberculosis]
gi|2742942721|ref|WP_349438767.1|

Protein
MptD family putative ECF transporter S component [Peptoniphilus sp. BV3C26]
MptD family putative ECF transporter S component [Peptoniphilus sp. BV3C26]
gi|553309678|ref|WP_023054716.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000793516	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Aug 18, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23798014, 26385305, 15210884 Citation Link,
SCV000915778	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Nov 20, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16488171, 27246109, 28755359, 25655073 Citation Link,
SCV001156591	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Jul 22, 2019)	germline	clinical testing	Citation Link,
SCV001364916	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 (2) [See all records that cite these PMIDs] 15210884, 25741868
SCV001459250	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002050776	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 6, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28755359, 15210884, 33150772, 32655480 Citation Link,
SCV002164258	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23798014, 25655073, 28755359, 32655480, 15210884, 28492532
SCV004214029	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 19, 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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis.

Boneh A, Andresen BS, Gregersen N, Ibrahim M, Tzanakos N, Peters H, Yaplito-Lee J, Pitt JJ.

Mol Genet Metab. 2006 Jun;88(2):166-70. Epub 2006 Feb 20.

PubMed [citation]

PMID:: 16488171

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000793516.1

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

#	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 Illumina Laboratory Services, Illumina, SCV000915778.1

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

Description

The ACADVL c.1156C>T (p.Arg385Trp) is a missense variant that has been reported in at least five studies and found in at least five individuals with VLCAD deficiency, including a sibling pair, in a compound heterozygous state with a unique missense variant in each case (Boneh et al. 2006; Wasibren et al. 2013; Yamamoto et al. 2015; Evans et al. 2016; Merinero et al. 2017). This variant was inherited from the unaffected mother in a heterozygous state (Merinero et al. 2017) and is reported at a frequency of 0.000208 in the Latino population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg386Cys variant is classified as likely pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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, SCV001156591.2

#	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.1153C>T; p.Arg385Trp variant (rs745832866), also reported as Arg345Trp, has been described in multiple individuals in association with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD; Boneh 2006, Merinero 2018, Ohashi 2004, Yamamoto 2015). It contains an entry in ClinVar (Variation ID: 193786), and is observed at a low overall frequency of 0.004% (10/251484 alleles) in the Genome Aggregation Database. The arginine at codon 385 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, recombinant ACADVL protein harboring the p.Arg385Trp substitution showed a reduction in enzyme activity comparted to wildtype (Ohashi 2004). Based on available information, this variant is considered likely pathogenic. REFERENCES Boneh et al. VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis. Mol. Genet. Metab. 2006; 88(2): 166-170. Merinero B et al. Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. JIMD Rep. 2018;39:63-74. Ohashi et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004; 62(12): 2209-2213. Yamamoto H et al. Successful management of pregnancy with very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Obstet Gynaecol Res. 2015 Jul;41(7):1126-8.

#	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, SCV001364916.2

#	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.1153C>T (NP_000009.1:p.Arg385Trp) [GRCH38: NC_000017.11:g.7223208C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 15210884. 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., SCV001459250.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002050776.1

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

Description

Variant summary: ACADVL c.1153C>T (p.Arg385Trp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251484 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (4e-05 vs 0.0029), allowing no conclusion about variant significance. c.1153C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example Ohashi_2004, Merinero_2018, Musumeci_2020, Chen_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Ohashi_2004, Chen_2020). The most pronounced variant effect results in a reduction in enzyme activity compared to wild type. Consistently, another recent study utilized this variant as a positive control to demonstrate a barely detectable level of fatty acid oxidation (FAO) activity as determined by overexpression of the recombinant HAtagged mutant proteins in HEK293T cell lines (Chen_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic/pathogenic, n=4; VUS, n=3). 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002164258.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 385 of the ACADVL protein (p.Arg385Trp). This variant is present in population databases (rs745832866, gnomAD 0.02%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23798014, 25655073, 28755359, 32655480). This variant is also known as R345W. ClinVar contains an entry for this variant (Variation ID: 193786). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 15210884). 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 Baylor Genetics, SCV004214029.2

#	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: Oct 13, 2024

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