Submissions for variant NM_000018.4(ACADVL):c.1700G>A (p.Arg567Gln)

gnomAD frequency: 0.00014  dbSNP: rs398123084

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000813614	SCV000953981	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 567 of the ACADVL protein (p.Arg567Gln). This variant is present in population databases (rs398123084, gnomAD 0.02%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23480858; 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: 92278). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 23480858). This variant disrupts the p.Arg567 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 28600779), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000813614	SCV001140233	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000813614	SCV001158615	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-11-09	criteria provided, single submitter	clinical testing	The ACADVL c.1700G>A; p.Arg567Gln variant (rs398123084) is reported in the literature in an individual with elevated acylcarnitine levels (Schiff 2013). In testing performed at ARUP Laboratories, this variant has also been observed in at least one individual with an abnormal newborn screen for VLCAD deficiency that also carried an additional pathogenic variant. The p.Arg567Gln variant is reported in ClinVar (Variation ID: 92278), and it is found in the general population with an overall allele frequency of 0.01% (23/210246 alleles) in the Genome Aggregation Database. The arginine at codon 567 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.876). In a biochemical VLCAD activity assay, the p.Arg567Gln variant protein exhibits 21% of wildtype activity (Schiff 2013). While this reduced activity may be attributable to reduced enzyme synthesis or stability by an uncertain mechanism, the decreased activity in the biochemical assay is consistent with reduced VLCAD activity measured in patient fibroblasts (Schiff 2013). Based on available information, the p.Arg567Gln variant is considered to be likely pathogenic. References: Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7. PMID: 32778825.
CeGaT Center for Human Genetics Tuebingen	RCV000259048	SCV001247040	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000813614	SCV001364939	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1700G>A (NP_000009.1:p.Arg567Gln) [GRCH38: NC_000017.11:g.7224663G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 23480858. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Baylor Genetics	RCV000813614	SCV001522462	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-09-30	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000813614	SCV002021274	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-05-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000813614	SCV002103815	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-02-21	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1700G>A (p.Arg567Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 179722 control chromosomes (gnomAD), predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00011 vs 0.0029), allowing no conclusion about variant significance. c.1700G>A has been reported in the literature in multiple compound heterozygous individuals (example: Ficicioglu_2010, Schiff_2013, Knottnerus_2020) and at least one homozygous individual (Alhashem_2020) affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. These data indicate that the variant is very likely to be associated with disease. One publication using a prokaryotic gene expression assay has reported that the variant had 21% ACADVL protein expression compared to wildtype (Schiff_2013). This however, does not allow convincing conclusions about the variant effect on protein function. Eight ClinVar submitters have assessed the variant since 2014: three have classified the variant as pathogenic, four as likely pathogenic, and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000813614	SCV003807061	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-08-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 supporting, PM3 moderated, PP3 supporting, PP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000259048	SCV004224167	pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PS3, PS4_moderate
Eurofins Ntd Llc (ga)	RCV000259048	SCV000109738	uncertain significance	not provided	2018-08-24	flagged submission	clinical testing
Natera, Inc.	RCV000813614	SCV002088811	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-08-26	no assertion criteria provided	clinical testing