Submissions for variant NM_000018.4(ACADVL):c.538G>A (p.Ala180Thr)

gnomAD frequency: 0.00001  dbSNP: rs727503791

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000675106	SCV002769742	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-04-23	reviewed by expert panel	curation	The c.538G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 180 (p.Ala180Thr). This variant has been reported in patients affected with very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and elevated C14:1 and reduced VLCAD activity measured in patient lymphocytes (PP4_Moderate, PMID: 26385305, 31844625, 32778825, 30194637). At least one individual was compound heterozygote with a second ACADVL variant, at least one of these variants is confirmed in trans and approved by the ACADVL VCEP as likely pathogenic (PM3, 1 point, PMID: 31844625, 30194637). 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) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 14, 2022 and the recurated classification was approved by the expert panel on April 23, 2023.
Eurofins Ntd Llc (ga)	RCV000152735	SCV000202122	uncertain significance	not provided	2017-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000152735	SCV000238635	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32798077, 26385305, 29268767, 30194637, 32778825)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000675106	SCV000602371	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2018-11-13	criteria provided, single submitter	clinical testing	The ACADVL c.538G>A; p.Ala180Thr variant (rs727503791) is reported in the literature to be significantly enriched in patients with abnormal newborn screening results suggestive of VLCAD deficiency (Miller 2015). This variant is reported in ClinVar (Variation ID: 166641), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at residue 180 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ala180Thr variant is considered to be likely pathogenic. References: Miller M et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015; 116(3):139-45.
Counsyl	RCV000675106	SCV000800653	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2018-01-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675106	SCV001233673	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 180 of the ACADVL protein (p.Ala180Thr). This variant is present in population databases (rs727503791, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency and/or very long-chain acyl-CoA dehydrogenase deficiency and a positive newborn screening result for ACADVL-related disease (PMID: 26385305, 30194637, 32798077; Invitae). 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: 166641). 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	RCV000675106	SCV001365220	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.538G>A (NP_000009.1:p.Ala180Thr) [GRCH38: NC_000017.11:g.7221598G>A] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM1, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000675106	SCV002765914	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-11-12	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.538G>A (p.Ala180Thr) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251462 control chromosomes (gnomAD). c.538G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Miller_2015, Janzen_2017, Hesse_2018). These data do not allow any conclusion about variant significance. Analysis of lymphocytes from a compound heterozygous patient with 2 missense variants, including the variant of interest, showed approximately 3% residual activity, indicating both variants were loss-of-function (Hesse_2018). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000675106	SCV003822476	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000675106	SCV004215125	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-02	criteria provided, single submitter	clinical testing