ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.637G>A (p.Ala213Thr) (rs140629318)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723371 SCV000232457 pathogenic not provided 2014-09-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000180089 SCV000406315 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2017-04-27 criteria provided, single submitter clinical testing The ACADVL c.637G>A (p.Ala213Thr) variant was identified in a homozygous state in three affected siblings with mild late-onset very long-chain-acyl-CoA dehydrogenase (VLCAD) deficiency (two of whom were identical twins) from a consanguineous family (Straussberg et al. 2002). In a second study, Zhang et al. (2014) reported the p.Ala213Thr variant in heterozygous state in an affected individual who also carried a second missense variant in a heterozygous state; phase information was not provided. Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the total population of the Exome Aggregation Consortium. Based on the evidence, the p.Ala173Thr variant is classified as a variant of unknown 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.
Invitae RCV000180089 SCV000823384 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 213 of the ACADVL protein (p.Ala213Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs140629318, ExAC 0.009%). This variant has been reported to segregate with very long chain acyl-CoA dehydrogenase deficiency in a family (PMID: 12213615) and has been reported in combination with another ACADVL variant in individuals affected with this condition (PMID: 24801231, 12213615). This variant is also known as G627A, p.Ala173Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 198683). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala213 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10077518), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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