ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1097G>A (p.Arg366His) (rs112406105)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000185720 SCV000883344 pathogenic not provided 2017-12-14 criteria provided, single submitter clinical testing
Counsyl RCV000411732 SCV000486429 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2016-05-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185720 SCV000860790 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
GeneDx RCV000185720 SCV000238645 pathogenic not provided 2016-06-09 criteria provided, single submitter clinical testing The R366H missense variant has been reported previously in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in several unrelated individuals who were homozygous for R366H, or heterozygous for R366H and another pathogenic variant in the ACADVL gene (Antunes et al., 2013; Andresen et al., 1999; Gobin-Limballe et al., 2010; Evans et al., 2016). The R366H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R366C) and a nearby residue (Q368P) have been reported in the Human Gene Mutation Database in association with VLCAD deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore we interpret R366H to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000411732 SCV000915777 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-01-09 criteria provided, single submitter clinical testing The ACADVL c.1097G>A (p.Arg366His) missense variant has been reported in at least four studies in which it is identified in at least seven individuals with VLCAD deficiency including in a homozygous state in one individual, in a compound heterozygous state in three individuals, in cis with another missense variant, both of which are in trans with a third missense variant in one individual, and in a heterozygous state in two individuals in whom it is unclear if they carry a second variant (Andresen et al. 1999; Boneh et al. 2006; Antunes et al. 2013; Evans et al. 2016). The p.Arg366His variant was absent from 100 control alleles and is reported at a frequency of 0.000098 in the South Asian population of the Genome Aggregation Database. Biochemical studies confirmed the VLCAD deficiency in all patients. Western blot analysis revealed reduced or barely detectable protein levels in fibroblasts from a patient carrying the p.Arg366His variant (Andresen et al. 1999). Several studies note that the variant is associated with a milder phenotype (Gobin-Limballe et al. 2010; Antunes et al. 2013; Brown et al. 2014). Structural analysis of the VLCAD protein suggests that the p.Arg366His variant would induce major structural alterations in substrate-binding, FAD-binding and in enzyme monomer-monomer interactions (Gobin-Limballe et al. 2010). The Arg366 site is thought to be a potential hotspot for variants (Andresen et al. 1999). Based on the collective evidence, the p.Arg366His 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.
Invitae RCV000411732 SCV000836322 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-05-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 366 of the ACADVL protein (p.Arg366His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs112406105, ExAC 0.006%). This variant has been observed as homozygous or in combination with another pathogenic ACADVL variant in several individuals affected with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 20060901, 24263034, 27246109 ). This variant is also known as p.Arg326His in the literature. ClinVar contains an entry for this variant (Variation ID: 203580). 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. The p.Arg366 amino acid residue in ACADVL has been determined to be clinically significant (PMID: 8845838, 21932095, 9973285, Invitae). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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