ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.562G>A (p.Gly188Ser)

dbSNP: rs2071231356
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV001040243 SCV002576784 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2023-04-11 reviewed by expert panel curation The c.562G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by serine at amino acid 188 (p.Gly188Ser). Information provided to the ACADVL VCEP provided by an external clinical laboratory shows increased C14:1 level in a pattern consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in one patient (PP4_moderate) who was homozygous for the variant (PM3_supporting). One publication describes this variant in an affected individual, but this individual does not meet our PP4 guidelines and was not counted (Nikolayeva, E.A. et al., Symptomatic epilepsy as a manifestation of very long chain acyl-CoA dehydrogenase deficiency. 2008. Rossiiskii Vestnik Perinatologii i Pediatrii 53(3): 87-91 (in Russian)). This variant is absent from gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.882, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PM3_supporting, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated April 12, 2022 and the recurated classification was approved by the expert panel on April 11, 2023.
Invitae RCV001040243 SCV001203805 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 188 of the ACADVL protein (p.Gly188Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 28468868; Invitae; https://cyberleninka.ru/article/v/simptomaticheskaya-epilepsiya-kak-proyavlenie-defitsita-atsil-koa-degidrogenazy-zhirnyh-kislot-s-ochen-dlinnoy-uglerodnoy-tsepyu). This variant is also known as c.631G>A (p.Gly211Ser). ClinVar contains an entry for this variant (Variation ID: 838654). 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%. For these reasons, this variant has been classified as Pathogenic.

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