ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1591C>T (p.Arg531Trp) (rs146379816)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185729 SCV000202128 uncertain significance not provided 2013-11-25 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000208321 SCV000263752 uncertain significance Primary dilated cardiomyopathy 2015-11-16 criteria provided, single submitter clinical testing
Invitae RCV000652029 SCV000773889 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 531 of the ACADVL protein (p.Arg531Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs146379816, ExAC 0.08%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as p.Arg491Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 166647). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000652029 SCV000791958 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2017-06-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000185729 SCV000884951 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing The ACADVL c.1591C>T; p.Arg531Trp variant (also known as Arg491Trp) is published in the medical literature in at least two individuals with suspected very long-chain acyl-CoA dehydrogenase deficiency, with one individual carrying an additional pathogenic variant presumed to occur on the opposite chromosome (Ghosh 2017, Hoffmann 2012). The variant is listed in the ClinVar database (Variation ID: 166647), in the dbSNP variant database (rs146379816), in the Exome Variant Server with an allele frequency of 0.0538 percent (7/12999 alleles), and in the Genome Aggregation Consortium with an allele frequency of 0.04416 percent (122/276294 alleles). The arginine at this position is moderately conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Ghosh A et al. Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing Arch Dis Child. 2017 102:1019-1029. 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.
Illumina Clinical Services Laboratory,Illumina RCV000652029 SCV000914788 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-08-09 criteria provided, single submitter clinical testing The ACADVL c.1591C>T (p.Arg531Trp) variant is a missense variant that has been reported in a compound heterozygous state with a canonical splice site variant in one individual with VLCAD deficiency who had residual enzyme activity of 21% (Hoffman et al. 2017). It has also been identified in a heterozygous state in four individuals with suspected VLCAD deficiency in whom a second variant was not identified (Miller et al. 2015; Ghosh et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000806 in the European (non-Finnish) population of the the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg531Trp variant is therefore classified as a variant of uncertain significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV000652029 SCV001163426 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192883 SCV001361315 uncertain significance not specified 2019-03-11 criteria provided, single submitter clinical testing Variant summary: ACADVL c.1591C>T (p.Arg531Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 276294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00044 vs 0.0029), allowing no conclusion about variant significance. c.1591C>T has been reported in the literature in individuals suspected to be affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency but with limited information (Ghosh_2017, Miller_2015). One study reported a compound heterozygote individual (IVS12+1G>A/p.R491W) was found to have enzyme activity of 21% and referred p.R491W as a milder mutation (Hoffmann_2012). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000652029 SCV001365228 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1591C>T (NP_000009.1:p.Arg531Trp) [GRCH38: NC_000017.11:g.7224379C>T] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM3, PP3, PP4

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