ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1127T>C (p.Phe376Ser)

gnomAD frequency: 0.00001  dbSNP: rs758928307
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000652042 SCV000602363 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2022-02-08 criteria provided, single submitter clinical testing The ACADVL c.1127T>C; p.Phe376Ser variant (rs758928307) is reported in the literature in several individuals affected with diagnosed or suspected VLCAD deficiency, each of whom carried a second missense variant (Merinero 2018, Rovelli 2019). This variant is found in the Latino population with an allele frequency of 0.01% (3/34586 alleles) in the Genome Aggregation Database. The phenylalanine at codon 376 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.889). However, due to limited information, the clinical significance of the p.Phe376Ser variant is uncertain at this time. References: Merinero et al. Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. JIMD Rep. 2018;39:63-74. PMID: 28755359. Rovelli et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081.
Invitae RCV000652042 SCV000773906 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 376 of the ACADVL protein (p.Phe376Ser). This variant is present in population databases (rs758928307, gnomAD 0.009%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 28755359, 31031081). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203581). 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000652042 SCV001365079 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1127T>C (NP_000009.1:p.Phe376Ser) [GRCH38: NC_000017.11:g.7223182T>C] 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
Mendelics RCV000652042 SCV002517504 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-05-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV000652042 SCV004216891 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-06-20 criteria provided, single submitter clinical testing
Natera, Inc. RCV000652042 SCV002088780 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2020-11-13 no assertion criteria provided clinical testing

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