ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1182+1G>A (rs113690956)

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Total submissions: 9
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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 2020-09-23 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000001689 SCV001156592 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-07-15 criteria provided, single submitter clinical testing The ACADVL c.1182+1G>A variant (rs113690956), is reported in the literature in the homozygous or compound heterozygous state in individuals affected with very long-chain acyl-coenzyme A dehydrogenase deficiency (Hoffmann 2012, Pena 2016, Strauss 1995). This variant is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 11, which is likely to disrupt gene function. Based on available information, the c.1182+1G>A variant is considered to be pathogenic. References: Hoffmann L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. Strauss AW et al. Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in childhood. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10496-500.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000001689 SCV001364917 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1182+1G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7223238G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:7479827. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001689 SCV001437389 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-09-08 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1182+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251464 control chromosomes. c.1182+1G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Strauss_1995, Pena_2016). At least one publication cites experimental evidence evaluating an impact on protein function. The most pronounced variant effect is cited as deficient mitochondrial dehydrogenase activity against palmitoyl-CoA, no immunoreactive VLCAD protein detected in fibroblast extracts and biosynthetic studies demonstrating rapid degradation of a slightly smaller, immunoreactive mutant VLCAD (Strauss_1995). Additionally, a residual enzyme activity of 50% has been reported as expected for a presumed carrier individual (Hoffmann_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000210824 SCV001714578 pathogenic not provided 2020-02-21 criteria provided, single submitter clinical testing
OMIM RCV000001689 SCV000021845 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 1995-11-07 no assertion criteria provided literature only

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