Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000556767 | SCV002769772 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-11-28 | reviewed by expert panel | curation | The c.652G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 218 (p.Glu218Lys, also known as Glu178Lys in traditional nomenclature). At least two patients with this variant displayed elevated C14:1 by newborn screen and/or reduced very long chain acyl CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 34184355, 30194637). Of those individuals, one was homozygous for the variant, confirmed by parental testing, and one was presumed in trans to a pathogenic variant (PM3 1 point; PMIDs: 34184355, 30194637). Additionally, one patient carrying this variant displayed a reduced VLCAD protein level (PMID: 9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000032 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 15, 2022 and the recurated classification was approved by the expert panel on November 13, 2023. |
| Invitae | RCV000556767 | SCV000654961 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 218 of the ACADVL protein (p.Glu218Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with very long chain acyl co-A dehydrogenase deficiency (PMID: 9973285, 30194637; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Glu178Lys. ClinVar contains an entry for this variant (Variation ID: 474901). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV000556767 | SCV002780521 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2021-10-16 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000556767 | SCV003800885 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-01-11 | criteria provided, single submitter | clinical testing | Variant summary: ACADVL c.652G>A (p.Glu218Lys) results in a conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251352 control chromosomes. c.652G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) (example, Andresen_1999, Hesse_2018, Takizaki_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 2% of normal VLCAD enzyme activity in leukocytes from a homozygous individual affected with VLCAD deficiency. Two clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=2; VUS, n=1). The expert panel classification as a VUS has cited overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000556767 | SCV004210789 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-09-26 | criteria provided, single submitter | clinical testing |