ClinVar Miner

Submissions for variant NM_025207.5(FLAD1):c.1588C>T (p.Arg530Cys)

gnomAD frequency: 0.00005  dbSNP: rs771466122
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Research Unit for Molecular Medicine, Department for Clinical Medicine, Aarhus University RCV000223948 SCV000266357 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2016-03-14 criteria provided, single submitter research
GeneDx RCV000521126 SCV000618447 pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing The R530C variant in the FLAD1 gene has previously been reported in two individuals with adult onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency who were compound heterozygous for frameshift variants in FLAD1 (Olsen et al., 2016). Functional analysis of R530C found that is is associated with higher sensitivity to proteolytic degradation and significantly reduced catalytic activity compared to wild-type (Olsen et al., 2016). The R530C 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). The R530C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret R530C to be a pathogenic variant.
Preventiongenetics, part of Exact Sciences RCV003407734 SCV004113669 likely pathogenic FLAD1-related condition 2023-02-21 criteria provided, single submitter clinical testing The FLAD1 c.1588C>T variant is predicted to result in the amino acid substitution p.Arg530Cys. This variant was reported in at least 3 individuals with multiple acyl-CoA dehydrogenase deficiency and multiple respiratory-chain deficiency (Olsen et al. 2016. PubMed ID: 27259049; Auranen et al. 2017. PubMed ID: 28433476; Muru et al. 2019. PubMed ID: 31392824). Functional studies suggest that the p.Arg530Cys substitution impacts the normal FLAD1protein function (Olsen et al. 2016. PubMed ID: 27259049). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-154965222-C-T). This variant is interpreted as likely pathogenic.
Invitae RCV000521126 SCV004292889 pathogenic not provided 2023-02-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 530 of the FLAD1 protein (p.Arg530Cys). This variant is present in population databases (rs771466122, gnomAD 0.005%). This missense change has been observed in individual(s) with FLAD1-related conditions (PMID: 27259049, 31392824). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224729). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FLAD1 function (PMID: 27259049). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000234835 SCV000292023 pathogenic Myopathy with abnormal lipid metabolism 2019-09-10 no assertion criteria provided literature only

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