ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1468G>C (p.Ala490Pro)

gnomAD frequency: 0.00001  dbSNP: rs759775666
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV000554101 SCV003936885 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-04-11 reviewed by expert panel curation The c.1468G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 490 (p.Ala490Pro), also known as Ala450Pro when numbered from the mature protein. This variant has been detected in at least 5 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 2 were compound heterozygous for the variant and distinct pathogenic or likely pathogenic variant, presumed to be in trans (PM3_Supporting, PMID: 26453363, 30194637). This variant has been described in at least 3 unrelated individuals who displayed VLCAD enzyme activity <20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:26453363, 14517516, 30194637). The variant has been reported to segregate with VLCAD deficiency in 2 affected siblings from 1 family (PP1, PMID: 14517516). This variant resides within a region, amino acids 481-516, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PMID: 18227065, 20060901). A substrate specificity assay showed this variant displays abnormal substrate specificity; however, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9839948). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.794, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_Supporting, PM3_Supporting, PP1, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).
Labcorp Genetics (formerly Invitae), Labcorp RCV000554101 SCV000654935 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 490 of the ACADVL protein (p.Ala490Pro). This variant is present in population databases (rs759775666, gnomAD 0.004%). This missense change has been observed in individual(s) with known or suggested very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 10077518, 14517516, 26453363). This variant is also known as A450P. ClinVar contains an entry for this variant (Variation ID: 474888). 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: 17374501). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000554101 SCV000789050 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-12-28 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000554101 SCV001364932 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1468G>C (NP_000009.1:p.Ala490Pro) [GRCH38: NC_000017.11:g.7224179G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9839948; 10077518. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000554101 SCV001571361 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-04-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000554101 SCV004210944 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2024-03-20 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004754471 SCV005346707 likely pathogenic ACADVL-related disorder 2024-08-23 no assertion criteria provided clinical testing The ACADVL c.1468G>C variant is predicted to result in the amino acid substitution p.Ala490Pro. This variant was reported in multiple patients with clinical and biochemical features consistent with Very long chain acyl-CoA dehydrogenase deficiency (Diekman et al. 2015. PubMed ID: 26453363, Spiekerkoetter et al. 2003. PubMed ID: 14517516, Mathur et al. 1999. PubMed ID: 10077518, Goetzman et al. 2007. PubMed ID: 17374501). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD, and is interpreted as likely pathogenic by the ClinGen ACADVL Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/474888/). This variant is interpreted as likely pathogenic.

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