NM_000018.4(ACADVL):c.848T>C (p.Val283Ala) AND Very long chain acyl-CoA dehydrogenase deficiency
- Germline classification:
- Pathogenic (21 submissions)
- Last evaluated:
- Aug 23, 2022
- Review status:
- 3 stars out of maximum of 4 starsreviewed by expert panel
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000020081.64
Allele description [Variation Report for NM_000018.4(ACADVL):c.848T>C (p.Val283Ala)]
NM_000018.4(ACADVL):c.848T>C (p.Val283Ala)
- 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.848T>C (p.Val283Ala)
- Other names:
- p.V283A:GTG>GCG; NM_000018.4(ACADVL):c.848T>C
- HGVS:
- NC_000017.11:g.7222272T>C
- NG_007975.1:g.7439T>C
- NG_008391.2:g.2779A>G
- NM_000018.4:c.848T>CMANE SELECT
- NM_001033859.3:c.782T>C
- NM_001270447.1:c.917T>C
- NM_001270447.2:c.917T>C
- NM_001270448.2:c.620T>C
- NP_000009.1:p.Val283Ala
- NP_000009.1:p.Val283Ala
- NP_001029031.1:p.Val261Ala
- NP_001257376.1:p.Val306Ala
- NP_001257377.1:p.Val207Ala
- NP_001257377.1:p.Val207Ala
- NC_000017.10:g.7125591T>C
- NM_000018.2:c.848T>C
- NM_000018.3:c.848T>C
- NM_000018.4:c.848T>C
- NM_001270448.1:c.620T>C
- P49748:p.Val283Ala
This HGVS expression did not pass validation- Protein change:
- V207A
- Links:
- UniProtKB: P49748#VAR_000342; dbSNP: rs113994167
- NCBI 1000 Genomes Browser:
- rs113994167
- Molecular consequence:
- NM_000018.4:c.848T>C - missense variant - [Sequence Ontology: SO:0001583]
- NM_001033859.3:c.782T>C - missense variant - [Sequence Ontology: SO:0001583]
- NM_001270447.2:c.917T>C - missense variant - [Sequence Ontology: SO:0001583]
- NM_001270448.2:c.620T>C - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 1
Condition(s)
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000040379 | GeneReviews | no classification provided | not provided | germline | literature only | |
| SCV000406318 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) | Pathogenic (Oct 18, 2017) | germline | clinical testing | |
| SCV000494238 | Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jun 27, 2016) | germline | clinical testing | |
| SCV000593009 | Genetic Services Laboratory, University of Chicago | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 2, 2016) | germline | clinical testing | |
| SCV000602354 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) | Pathogenic (Nov 3, 2023) | germline | clinical testing | |
| SCV000611159 | Fulgent Genetics, Fulgent Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 18, 2017) | unknown | clinical testing | |
| SCV000654971 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jan 31, 2024) | germline | clinical testing | |
| SCV000693967 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Jan 22, 2016) | germline | clinical testing | PubMed (4) LabCorp Variant Classification Summary - May 2015.docx, |
| SCV000711421 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (LMM Criteria) | Pathogenic (Aug 25, 2016) | germline | clinical testing | |
| SCV001163424 | Baylor Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 30, 2024) | unknown | clinical testing | |
| SCV001193828 | Myriad Genetics, Inc. | criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) | Pathogenic (Oct 18, 2019) | unknown | clinical testing | |
| SCV001364905 | 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 | |
| SCV001810249 | Genome-Nilou Lab | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jul 22, 2021) | germline | clinical testing | |
| SCV001977084 | Clinical Genetics Laboratory, Region Ostergotland | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Aug 17, 2020) | germline | clinical testing | |
| SCV002021118 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Sep 19, 2023) | germline | clinical testing | |
| SCV002088765 | Natera, Inc. | no assertion criteria provided | Pathogenic (Sep 23, 2017) | germline | clinical testing | |
| SCV002557011 | Genetics and Molecular Pathology, SA Pathology
| criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jul 20, 2020) | germline | clinical testing | |
| SCV002576760 | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | reviewed by expert panel (clingen acadvl acmg specifications v1) | Pathogenic (Aug 23, 2022) | germline | curation | |
| SCV002768698 | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
| criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jun 11, 2020) | germline | clinical testing | |
| SCV004697701 | Molecular Genetics Lab, CHRU Brest | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | inherited | clinical testing | |
| SCV005051755 | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Feb 1, 2024) | germline | curation |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, literature only, curation |
| not provided | inherited | yes | 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 |
| not provided | germline | no | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
| not provided | germline | not provided | 1 | 1 | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening.
Merritt JL 2nd, Vedal S, Abdenur JE, Au SM, Barshop BA, Feuchtbaum L, Harding CO, Hermerath C, Lorey F, Sesser DE, Thompson JD, Yu A.
Mol Genet Metab. 2014 Apr;111(4):484-92. doi: 10.1016/j.ymgme.2014.01.009. Epub 2014 Jan 23.
- PMID:
- 24503138
Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency..
Leslie ND, Saenz-Ayala S.
2009 May 28 [updated 2023 Jul 13]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.
- PMID:
- 20301763
Details of each submission
From GeneReviews, SCV000040379.4
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | PubMed (3) |
Description
The most common pathogenic variant; accounts for about 10%-29% of all pathogenic alleles
| # | 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 Illumina Laboratory Services, Illumina, SCV000406318.3
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (9) |
Description
The ACADVL c.848T>C (p.Val283Ala) variant, also referred to as c.917T>C (p.Val306Ala), is one of the most common pathogenic variants and accounts for approximately 20% of disease-causing alleles among individuals with VLCAD deficiency ascertained by newborn screening (Leslie et al. 2014). Across a selection of the available literature, the p.Val283Ala variant was identified in a total of 20 individuals with VLCAD deficiency, including two homozygotes, 17 compound heterozygotes, and one heterozygote (Andresen et al. 1996; Andresen et al. 1999; Shchelochkov et al. 2009; Coughlin et al. 2010; McGoey et al. 2011; Schiff et al. 2013; Merritt et al. 2014). The phenotypic spectrum of these individuals ranged from asymptomatic to severe. The variant was absent from 51 control individuals, but is reported at a frequency of 0.00241 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression studies in prokaryotic and mammalian cells showed that the p.Val283Ala variant had enzyme activity of 20%-25% of the wild type (Andresen et al. 1999; Goetzman et al. 2007). Based on the evidence, the p.Val283Ala variant is classified as 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 Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000494238.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
The c.848T>C (p.Val283Ala) missense variant in the ACADVL gene has been previously reported in numerous individuals affected with VLCAD deficiency with both the mild and severe types depending on the other variants the patients harbored, and is thus considered a common pathogenic variant associated with VLCAD deficiency (Andresen et al., 1996; Andresen et al., 1999; Boneh et al., 2006; Coughlin et al., 2010; Hoffmann et al., 2012; Miller et al., 2015). This variant is often observed in trans with other pathogenic variants in affected individuals (Boneh et al., 2006; Coughlin et al., 2010; Hoffmann et al., 2012). Furthermore, functional assays both in vitro and from patients have demonstrated that this variant resulted in reduced residual enzymatic activity (Andresen et al., 1999; Goetzman et al., 2007; Hoffmann et al., 2012). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.128%; 1000 Genomes = NA; and ExAC = 0.24%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 5.22; CADD = 21.8; SIFT = 0.0). Multiple reputable diagnostic laboratories have classified this variant as Pathogenic (Emory, GeneDx). Therefore, this collective evidence supports the classification of the c.848T>C (p.Val283Ala) as a Pathogenic variant for VLCAD deficiency. We have confirmed this finding in our laboratory using Sanger sequencing.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Genetic Services Laboratory, University of Chicago, SCV000593009.1
| # | 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 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602354.10
| # | 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.848T>C; p.Val283Ala variant (rs113994167), also known as p.Val243Ala, is reported the literature in individuals affected with VLCAD deficiency (Andresen 1996) and accounts for 20% of all pathogenic alleles in VLCAD individuals identified by newborn screening (Leslie 2009). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 21025) and functional studies demonstrate that this variant reduces the amount of ACADVL protein produced, which causes a decrease in enzymatic activity (Andresen 1999, Goetzman 2007). Based on available information, this variant is considered to be pathogenic. References: Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. PMID: 9973285. Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996 Apr;5(4):461-72. PMID: 8845838. Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. Epub 2007 Mar 19. PMID: 17374501. Leslie ND et al. 2009 May 28 [Updated 2014 Sep 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6816/. PMID: 20301763.
| # | 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, SCV000611159.1
| # | 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, SCV000654971.9
| # | 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 valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 283 of the ACADVL protein (p.Val283Ala). This variant is present in population databases (rs113994167, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and is associated with a wide range of clinical presentations (PMID: 14517516, 17999356, 20107901). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as V243A. ClinVar contains an entry for this variant (Variation ID: 21025). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADVL protein function. Experimental studies have shown that this missense change affects ACADVL function (PMID: 9973285, 17374501). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000693967.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (4) |
Description
Variant summary: The c.848T>C in ACADVL gene is a missense variant that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is present in the broad control population dataset of ExAC at a low frequency (0.14%), which does not exceed the maximum frequency for a pathogenic variant in ACADVL gene (0.29%), suggesting this variant is not a common polymorphism. The variant has been reported in multiple affected individuals presented with Very-long-chain acyl-coenzyme A dehydrogenase deficiency. It is one of the most common pathogenic alleles that accounts for approximately 20% of all pathogenic alleles among individuals detected by newborn screening. This variant is considered to be a mild mutation with residual enzymatic activity ranging between 10%-22%. The variant of interest has been reported as Pathogenic by several reputable databases/diagnostic centers. Taking together, 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711421.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (7) |
Description
The p.Val283Ala variant in ACADVL has been reported in several patients with ver y long chain acyl-CoA dehydrogenase deficiency in the homozygous or compound het erozygous state (Andresen 1996, Andresen 1999, Coughlin 2010, Hoffmann 2012, Sch woerer 2015). It has been generally associated with a milder phenotype (Spiekerk oetter 2009). This variant has also been identified in 0.24% (160/66534) of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP 113994167). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequen cy. In addition, in vitro functional studies provide some evidence that the p.Va l283Ala variant may impact protein function (Andresen 1999, Goetzman 2007). In s ummary, this variant meets criteria to be classified as pathogenic for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner based upon case studies, low frequency in controls and functional evidence.
| # | 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 | 1 | not provided | 1 | not provided | |
From Baylor Genetics, SCV001163424.2
| # | 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 | |
From Myriad Genetics, Inc., SCV001193828.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (4) |
Description
NM_000018.3(ACADVL):c.848T>C(V283A, aka V243A) is classified as pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. Sources cited for classification include the following: PMID 9973285, 21932095, 8845838, and 17374501. Classification of NM_000018.3(ACADVL):c.848T>C(V283A, aka V243A) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. 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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364905.2
| # | 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.848T>C (NP_000009.1:p.Val283Ala) [GRCH38: NC_000017.11:g.7222272T>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8845838; 26385305. 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 Genome-Nilou Lab, SCV001810249.1
| # | 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 | germline | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Clinical Genetics Laboratory, Region Ostergotland, SCV001977084.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
PS4, PM1, PM2, PM3, PP5
| # | 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 Revvity Omics, Revvity, SCV002021118.3
| # | 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 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Natera, Inc., SCV002088765.1
| # | 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 Genetics and Molecular Pathology, SA Pathology, SCV002557011.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (6) |
Description
The ACADVL c.848T>C variant is classified as PATHOGENIC (PS4, PS3, PP5, PP3) The ACADVL c.848T>C variant is a single nucleotide substitution from a thymine to cytosine at position 848 which is predicted to change the valine at position 283 in the protein to alanine. This variant has been previously referred to as p.V243A and is the most common variant associated with VLCAD deficiency (PMID: 9973285, 27209629, 31031081) (PS4). Multiple functional studies have demonstrated that this variant is associated with approximately 20% residual enzyme activity, resulting in a milder phenotype (PMID: 9973285, 17374501, 21932095) (PS3). The variant is in dbSNP (rs113994167) and has been reported in population databases (gnomAD 346/282744, 2 homozygotes). The variant has been reported in the ClinVar database as pathogenic by multiple diagnostic laboratories (Var ID 21025) and has been reported in the HGMD database (CM960004) (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3).
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002576760.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | not provided |
Description
The c.848T>C variant in ACADVL is a missense variant predicted to cause substitution of valine by alanine at amino acid 283 (p.Val283Ala). This variant is also known as Val243Ala when numbered from the mature peptide. The variant accounts for up to 29% of individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency identified by newborn screen (PMID:20301763). This variant has been reported in at least 12 individuals with VLCAD in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 17999356, 26385305, 20107901, 14517516). The variant was detected at least 9 times in the homozygous state as well as at least 1 confirmed in-trans with another pathogenic variant (PM3_Strong; PMID: 20107901; 17999356, 17999356). In vitro expression showed 20-25% residual enzyme activity when expressed in COS7 cells (PS3_supporting; PMID: 9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002238 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The variant is located in a well-studied outer loop with structural importance with high homology to medium-chain acyl-CoA dehydrogenase (PM1; PMID: 14517516). The computational predictor REVEL gives a score of 0.905, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM1, PP3, PS3_supporting (ACADVL specifications version 1; approved November 8, 2021)
| # | 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768698.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine (exon 9). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (342 Heterozygotes, 4 Homozygotes). (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. The variant is located in the Acyl-CoA dehydrogenase, N-terminal domain (Protein Data Bank). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar). (P) 1002 - Moderate functional evidence supporting abnormal protein function. E.coli expression mutant constructs had approximately 20% residual enzymatic activity compared with wild type constructs (PMID: 17374501). (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
| # | 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 Genetics Lab, CHRU Brest, SCV004697701.1
| # | 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 | inherited | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051755.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: Nov 24, 2024