Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000673457 | SCV004805221 | uncertain significance | Very long chain acyl-CoA dehydrogenase deficiency | 2024-03-26 | reviewed by expert panel | curation | The NM_000018.4 c.578G>A (p.Gly193Asp) in ACADVL is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 193 (p. Gly193Asp). The highest population minor allele frequency in gnomAD v4.0.0 is 0.000004 in Non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). |
Gene |
RCV000498240 | SCV000589793 | uncertain significance | not provided | 2023-09-20 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
Counsyl | RCV000673457 | SCV000798661 | uncertain significance | Very long chain acyl-CoA dehydrogenase deficiency | 2018-03-21 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000673457 | SCV003000348 | uncertain significance | Very long chain acyl-CoA dehydrogenase deficiency | 2021-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 193 of the ACADVL protein (p.Gly193Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. ClinVar contains an entry for this variant (Variation ID: 432108). 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. 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. |