ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1096C>T (p.Arg366Cys) (rs771874163)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185719 SCV000238644 pathogenic not provided 2015-03-23 criteria provided, single submitter clinical testing The R366C missense mutation identified in the ACADVL gene has been reported previously in association with VLCAD deficiency (Andresen et al., 1996). The variant is found in ACADVL panel(s).
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000185719 SCV000281260 pathogenic not provided 2014-05-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508196 SCV000602375 pathogenic not specified 2017-02-08 criteria provided, single submitter clinical testing
Counsyl RCV000675110 SCV000800658 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-01-30 criteria provided, single submitter clinical testing
Invitae RCV000675110 SCV000832501 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-05-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 366 of the ACADVL protein (p.Arg366Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs771874163, ExAC 0.02%). This variant has been reported in combination with two other ACADVL variants in an individual affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8845838, Invitae) and in affected individuals in whom no second allele was reported (PMID: 21932095, 9973285). In one of these individuals the variant was observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with this condition. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as p.Arg326Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 203579). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg366His) has been determined to be pathogenic (PMID: 24263034, 16488171, 20060901, 27246109) and is also known as p.Arg326His in the literature. This suggests that the arginine residue is critical for ACADVL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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