Submissions for variant NM_000018.4(ACADVL):c.1612C>T (p.Arg538Trp)

gnomAD frequency: 0.00001  dbSNP: rs192904909

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200777	SCV001365213	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1612C>T (NP_000009.1:p.Arg538Trp) [GRCH38: NC_000017.11:g.7224486C>T] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant dose not meet any evidence codes reported in the ACMG guidelines.
Invitae	RCV001200777	SCV001415681	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 538 of the ACADVL protein (p.Arg538Trp). This variant is present in population databases (rs192904909, gnomAD 0.02%). This missense change has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 932825). 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.
GeneDx	RCV001559434	SCV001781658	uncertain significance	not provided	2020-12-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001200777	SCV003799823	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-08-17	criteria provided, single submitter	clinical testing	The ACADVL c.1612C>T; p.Arg538Trp variant (rs192904909) is reported in the literature in the heterozygous state in an individual who underwent follow-up testing after an unspecified abnormal result on newborn screening (Adhikari 2020) and is reported in ClinVar (Variation ID: 932825). This variant is found in the Latino/Admixed American population with an allele frequency of 0.017% (6/34566 alleles) in the Genome Aggregation Database. The arginine at codon 538 is weakly conserved and computational analyses are uncertain whether this variant is deleterious or neutral (REVEL: 0.286). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. REFERENCES Adhikari AN et al. The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020 Sep;26(9):1392-1397. PMID: 32778825.
Natera, Inc.	RCV001200777	SCV002088805	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-05-15	no assertion criteria provided	clinical testing