ClinVar Miner

Submissions for variant NM_000018.2(ACADVL):c.1182+1G>A (rs113690956)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001689 SCV000220283 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-04-29 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000210824 SCV000225143 pathogenic not provided 2013-10-24 criteria provided, single submitter clinical testing
GeneDx RCV000210824 SCV000238647 pathogenic not provided 2018-05-24 criteria provided, single submitter clinical testing The c.1182+1 G>A pathogenic variant in the ACADVL gene has been reported previously in patients with VLCAD deficiency (Strauss et al. 1995; Hoffmann et al. 2012; Burrage et al. 2015). cDNA analysis found that c.1182+1 G>A results in skipping of exon 11, leading to an in-frame deletion of 35 amino acids (Strauss et al. 1995). The c.1182+1 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, we interpret c.1182+1 G>A as a pathogenic variant.
Invitae RCV000001689 SCV000654919 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-11-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the ACADVL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs113690956, ExAC 0.002%). This variant has been reported as homozygous or in combination with other ACADVL variants in individuals affected with VLCAD deficiency (PMID: 7479827, 27209629). This variant is also known as IVS11+1 in the literature. ClinVar contains an entry for this variant (Variation ID: 1622). Experimental analyses of fibroblasts from an affected individual homozygous for this variant showed that it causes the in-frame skipping of exon 11 and results in a loss of VLCAD protein expression (PMID: 7479827). In addition, another individual heterozygous of this variant showed 50% residual VLCAD enzyme activity in lymphocytes (PMID: 21932095). In summary, this variant is a rare splice site change which has been reported in affected individuals with evidence of disrupting RNA splicing and protein function. For these reasons, it has been classified as Pathogenic.
OMIM RCV000001689 SCV000021845 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1995-11-07 no assertion criteria provided literature only

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