Submissions for variant NM_000018.4(ACADVL):c.947G>A (p.Arg316Gln)

gnomAD frequency: 0.00006  dbSNP: rs147366714

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000755205	SCV000238641	uncertain significance	not provided	2016-07-21	criteria provided, single submitter	clinical testing	The R316Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R316Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000555764	SCV000602362	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-11-02	criteria provided, single submitter	clinical testing	The ACADVL c.947G>A; p.Arg316Gln variant (rs147366714) is not reported in the medical literature but is reported in ClinVar (Variation ID: 203577). This variant is found in the non-Finnish European population with an allele frequency of 0.005% (6/129026 alleles), in the Genome Aggregation Database. The arginine at codon 316 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.359). Due to limited information, the clinical significance of the p.Arg316Gln variant is uncertain at this time.
Invitae	RCV000555764	SCV000654975	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-16	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 316 of the ACADVL protein (p.Arg316Gln). This variant is present in population databases (rs147366714, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency (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: 203577). 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.
Illumina Laboratory Services, Illumina	RCV000555764	SCV001282785	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000555764	SCV001365203	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.947G>A (NP_000009.1:p.Arg316Gln) [GRCH38: NC_000017.11:g.7222735G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant dose not meet any evidence codes reported in the ACMG guidelines.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000555764	SCV002768676	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. The following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (Exon 10). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v3 <0.01 for a recessive condition (9 Heterozygotes, 0 Homozygotes). (P) 0309 - Alternative amino acid change at the same position has been observed in gnomAD (6 heterozygotes, 0 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif. The variant is in the Acyl-CoA dehydrogenase, middle domain (Protein Data Bank). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant is in the population at low frequency and has previously been described as variant of uncertain significance in multiple independent cases with consistent phenotype (ClinVar and PMID: 26385305) (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Baylor Genetics	RCV000555764	SCV004210822	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-03-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000555764	SCV001455132	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing