ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1322G>A (p.Gly441Asp) (rs2309689)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077903 SCV000225740 pathogenic not provided 2013-05-03 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077903 SCV000280823 pathogenic not provided 2014-11-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000020072 SCV000602359 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-30 criteria provided, single submitter clinical testing The ACADVL p.Gly441Asp variant has been described in the literature in individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and fibroblasts from at least one of these individuals have been shown to have reduced function (Andresen 1996, Gobin-Limballe 2010). The variant is listed in the dbSNP variant database (rs2309689) with an allele frequency 0.0008242 percent in the Exome Aggregation Consortium. The glycine at codon 441 is well conserved across species and computational programs (PolyPhen2, SIFT) predict this variant is deleterious to protein function. Taken together, this variant is considered pathogenic. REFERENCES Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996; 5(4):461-72. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010; 1802(5):478-84.
Invitae RCV000020072 SCV000654927 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 441 of the ACADVL protein (p.Gly441Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs2309689, ExAC 0.001%). This variant has been reported as homozygous and in combination with another VLCAD variant in multiple individuals affected with VLCAD deficiency (PMID: 8845838, 16443431, 24305961, 17999356). This variant is also known in the literature as p.Gly401Asp. ClinVar contains an entry for this variant (Variation ID: 21016). Experimental studies with fibroblasts from two individuals with this variant co-occurring with another pathogenic VLCAD variant, showed substantially reduced enzyme activity to less than 30% of the control level (PMID: 25834949) For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000020072 SCV000021852 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1998-04-01 no assertion criteria provided literature only
GeneReviews RCV000020072 SCV000040370 pathologic Very long chain acyl-CoA dehydrogenase deficiency 2011-09-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000020072 SCV000486487 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-05-04 no assertion criteria provided clinical testing

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