Submissions for variant NM_000018.4(ACADVL):c.227G>A (p.Gly76Glu)

gnomAD frequency: 0.00001  dbSNP: rs750043368

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669555	SCV000794318	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2017-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000669555	SCV000915775	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2017-09-06	criteria provided, single submitter	clinical testing	The ACADVL c.227G>A (p.Gly76Glu) variant has been reported in a compound heterozygous state with another missense variant in an individual who initially presented with elevated C14:1-carnitine levels (Schymik et al. 2006). Of note, this variant is reported as c.227G>A, but described as p.Gly36Gln in the study. This patient's mother was found to be heterozygous for the c.227G>A (p.Gly36Gln) variant and the father was heterozygous for the other variant. Control data are not available for the p.Gly76Glu variant which is reported at a frequency of 0.000121 in the South Asian population from the Exome Aggregation Consortium; however this is based on two alleles so the variant is presumed to be rare. VLCAD enzyme activity was measured in lymphocyte homogenates from the patient who was compound heterozygous for the c.227G>A (p.Gly36Gln) variant and no residual enzyme activity was detected. The evidence for this variant is limited. Therefore, the p.Gly76Glu variant is considered to be of unknown significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genome-Nilou Lab	RCV000669555	SCV001781304	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2021-07-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731870	SCV001983571	uncertain significance	not specified	2021-09-17	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.227G>A (p.Gly76Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.227G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Schymik_2006). This report does not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000669555	SCV002193147	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 76 of the ACADVL protein (p.Gly76Glu). This variant is present in population databases (rs750043368, gnomAD 0.006%). This missense change has been observed in individual(s) with very-long-chain acyl-CoA dehydrogenase deficiency (PMID: 16860141, 30194637). This variant is also known as G36Q. ClinVar contains an entry for this variant (Variation ID: 554006). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADVL protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002531230	SCV003742084	uncertain significance	Inborn genetic diseases	2022-01-19	criteria provided, single submitter	clinical testing	The c.227G>A (p.G76E) alteration is located in exon 4 (coding exon 4) of the ACADVL gene. This alteration results from a G to A substitution at nucleotide position 227, causing the glycine (G) at amino acid position 76 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000669555	SCV004175782	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-01	criteria provided, single submitter	clinical testing	The missense c.227G>A(p.Gly76Glu) variant in ACADVL gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with very-long-chain acyl-CoA dehydrogenase deficiency (Hesse J et al., 2018). This variant is reported with the allele frequency of 0.0008% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic. The amino acid Gly at position 76 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly76Glu in ACADVL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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) indicates that this missense variant is expected to disrupt ACADVL protein function. For these reasons, this variant has been classified as Likely Pathogenic. .
Baylor Genetics	RCV000669555	SCV004210353	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-11-09	criteria provided, single submitter	clinical testing