Submissions for variant NM_000018.4(ACADVL):c.887_888del (p.Pro296fs)

gnomAD frequency: 0.00001  dbSNP: rs753108198

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000169392	SCV003936877	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-06-13	reviewed by expert panel	curation	The c.887_888del (p.Pro296ArgfsTer17) variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has also been reported in patients with phenotypes suggestive of a fatty acid oxidation defect (PMIDs: 10077518, 32778825). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PVS1+PM2_supporting).
Counsyl	RCV000169392	SCV000220784	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2014-10-10	criteria provided, single submitter	literature only
GeneDx	RCV000185736	SCV000238664	pathogenic	not provided	2014-07-25	criteria provided, single submitter	clinical testing	The c.887_888delCT mutation has been reported previously in association with VLCAD deficiency (Mathur et al., 1999). The deletion causes a frameshift starting with codon Proline 296, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Pro296ArgfsX17. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in ACADVL panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169392	SCV000693968	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.887_888delCT (p.Pro296ArgfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250254 control chromosomes (gnomAD). c.887_888delCT has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Hesse_2018, Mathur_1999, Schiff_2013, Wang_2019). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000169392	SCV001201176	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro296Argfs*17) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (rs753108198, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23480858, 30194637). ClinVar contains an entry for this variant (Variation ID: 189008). For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000169392	SCV001364908	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.887_888delCT (NP_000009.1:p.Pro296ArgfsTer17) [GRCH38: NC_000017.11:g.7222675_7222676delCT] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 10077518. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
CeGaT Center for Human Genetics Tuebingen	RCV000185736	SCV002498233	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169392	SCV002809720	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-07-08	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000169392	SCV003924175	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-03-30	criteria provided, single submitter	clinical testing	ACADVL NM_000018.3 exon 10 p.Pro296Argfs*17 (c.887_888del): This variant has been reported in the literature in the homozygous or compound heterozygous state in multiple individuals with features of VLCAD deficiency (Schiff 2013 PMID:23480858, Hesse 2018 PMID:30194637, Wang 2019 PMID:31620161). Additionally, enzyme studies on fibroblast samples from two patients showed no detectible residual enzyme activity (Mathur 1999 PMID:10077518, Schiff 2013 PMID:23480858). This variant is present in 0.002% (1/34482) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-7125993-CCT-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or Likely Pathogenic (Variation ID:189008). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 17 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Andresen 1999 PMID:9973285). In summary, this variant is classified as pathogenic based on the data above.
Baylor Genetics	RCV000169392	SCV004215037	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-08-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169392	SCV002088767	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-04-29	no assertion criteria provided	clinical testing