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

gnomAD frequency: 0.00003  dbSNP: rs113994169

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020069	SCV000654921	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 409 of the ACADVL protein (p.Thr409Met). This variant is present in population databases (rs113994169, gnomAD 0.04%). This missense change has been observed, in combination with a different pathogenic ACADVL variant, in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) (PMID: 24503138, 31031081; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Maori and Pacific ancestry (PMID: 26743058). Homozygous individuals have been reported with abnormal newborn screening lab results but without early-onset or severe symptoms typical for classic VLCAD; however, long term follow-up data is not available to assess risk for late-onset VLCAD (PMID: 24503138). ClinVar contains an entry for this variant (Variation ID: 21013). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACADVL protein function with a negative predictive value of 80%. 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	2023-03-15	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 occurrence of late-onset VLCAD symptoms during adolescence or adulthood. This variant has more recently been reported to be compound heterozygous with other ACADVL variants in individuals with VLCAD deficiency (Rovelli 2019). The p.Thr409Met variant is reported in ClinVar (Variation ID: 21013). It is observed in the general population with an overall allele frequency of 0.005% (14/282856 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.333). Based on the available information, the clinical significance of this variant is uncertain at this time. References: Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. PMID: 27246109. Merritt JL et al. Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab. 2014 Apr;111(4):484-92. PMID: 24503138. Rovelli V 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. 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 May;39(3):409-414. PMID: 26743058.
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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020069	SCV002766631	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with VLCAD deficiency (MIM#201475). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 19 heterozygotes, 0 homozygotes,). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (I) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, C-terminal domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Thr409Arg) has been classified as a VUS by a diagnostic laboratory in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been classified as pathogenic and VUS by diagnostic laboratories in ClinVar. Known to be enriched in Polynesian populations, compound heterozygous individuals are likely to manifest mild disease and homozygotes tend to remain asymptomatic (PMID: 26743058, 35267200, 35400565). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Blood spots from individuals carrying this variant (both homozygous and compound heterozygous), consistently display VLCAD deficiency and elevated C14:1-carnitine levels (PMID:31031081, 26743058, 24503138). (SP) 1207 - Parental origin of the variant is unresolved. Subsequent analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002514121	SCV003679626	uncertain significance	Inborn genetic diseases	2022-12-29	criteria provided, single submitter	clinical testing	The c.1226C>T (p.T409M) alteration is located in exon 12 (coding exon 12) of the ACADVL gene. This alteration results from a C to T substitution at nucleotide position 1226, causing the threonine (T) at amino acid position 409 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.005% (14/282856) total alleles studied. The highest observed frequency was 0.069% (5/7226) of Other alleles. The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.T409 amino acid is not conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000020069	SCV003822474	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-01-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020069	SCV004214095	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000020069	SCV005650606	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2024-04-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000020069	SCV001459252	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing