ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.605T>A (p.Leu202His)

dbSNP: rs398123090
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000077920 SCV000109749 uncertain significance not provided 2012-12-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001444 SCV001158682 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2018-09-06 criteria provided, single submitter clinical testing The ACADVL c.605T>A; p.Leu202His variant (rs398123090), to our knowledge, is not reported in the medical literature but is reported as uncertain significance in ClinVar (Variation ID: 92287). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 202 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu202His variant is uncertain at this time.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001001444 SCV001365035 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.605T>A (NP_000009.1:p.Leu202His) [GRCH38: NC_000017.11:g.7221665T>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001001444 SCV004241864 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-12-06 criteria provided, single submitter clinical testing Variant summary: ACADVL c.605T>A (p.Leu202His) results in a non-conservative amino acid change located in the N-terminal domain (IPR013786) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251270 control chromosomes (gnomAD). c.605T>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Miller_2015, Rovelli_2019, Ambrose_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However other missense variants affecting the same amino acid have been reported in affected individuals (HGMD) and been classified as pathogenic by other laboratories in ClinVar, suggesting that this residue is critical for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 26385305, 31031081, 36109795). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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