ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1226C>T (p.Thr409Met)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000020069 SCV000654921 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 409 of the ACADVL protein (p.Thr409Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs113994169, ExAC 0.02%). This variant has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 27246109, 31031081, Invitae) and is commonly seen in asymptomatic individual(s) with abnormal newborn screens in Hawaii and New Zealand (PMID: 24503138, 25085675) and has also been seen in patients with confirmatory labs that are consistent with VLCAD deficiency (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21013). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000020069 SCV000883345 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-03-21 criteria provided, single submitter clinical testing The ACADVL c.1226C>T, p.Thr409Met variant (rs113994169) has been reported at a high frequency in unaffected individuals of Maori and Pacific ancestry (Ryder 2016). Homozygosity for this variant has been associated with elevated C14:1 acylcarnitine levels during newborn screening, but has not been associated with the development of classical very long-chain acyl CoA dehydrogenase (VLCAD) deficiency (Evans 2016, Merritt 2014, Ryder 2016). However, these studies did not evaluate the presence late-onset VLCAD symptoms during adolescence or adulthood. The p.Thr409Met variant is reported in ClinVar (Variation ID: 21013), and it is found in the general population with an overall allele frequency of 0.005% (14/282856 alleles) in the Genome Aggregation Database (15/277206 alleles). The threonine at codon 409 is weakly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. In consideration of the currently available literature, the clinical significance of the p.Thr409Met variant could not be determined with certainty. References: Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016; 118(4):282-7. Merritt J et al. Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab. 2014; 111(4):484-92. Ryder B et al. The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment. J Inherit Metab Dis. 2016; 39(3):409-14.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000020069 SCV001365207 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1226C>T (NP_000009.1:p.Thr409Met) [GRCH38: NC_000017.11:g.7223687C>T] 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: BP4
Natera, Inc. RCV000020069 SCV001459252 uncertain significance Very long chain acyl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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