ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1358G>A (p.Arg453Gln) (rs138058572)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415274 SCV000492897 likely pathogenic Myopathy; Rhabdomyolysis 2015-01-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091164 SCV001247037 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001075888 SCV001364922 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1358G>A (NP_000009.1:p.Arg453Gln) [GRCH38: NC_000017.11:g.7223993G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Invitae RCV001075888 SCV001391765 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 453 of the ACADVL protein (p.Arg453Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138058572, ExAC 0.01%). This variant has been observed in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 20060901, Invitae). ClinVar contains an entry for this variant (Variation ID: 374123). 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. For these reasons, this variant has been classified as Pathogenic.
Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences RCV001075888 SCV001241529 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-12-01 no assertion criteria provided research The variant was observed in two patients. The first patient is a 31-year-old Serbian woman who from non-consanguineous healthy parents who developed severe progressive fatigue during normal physical activities at age 26. CK level was 3180 IU/L, AST 344 (IU/L), and ALT 325 (IU/L). The cardiac evaluation and forced vital capacity were normal. During exacerbations, she could not walk on her toes and heels and had difficulties getting up from a squatting position. Through the course of the disease, CK levels varied between 90 and 9000 IU/L, and higher levels, paralleling clinical worsening. The second patient, sister of previous patient, 33-year-old, complained of mild fatigue during normal physical activities. On neurological examination, she had mild proximal weakness in her legs (MRC 5-/5) and CK was 67 U/L. Needle EMG showed spontaneous activities at rest and myopathic pattern during activation.

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