rs864321651

chr17-7224662-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000018.4(ACADVL):c.1699C>T(p.Arg567Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,342,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R567Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.67

Genes affected

ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 29) in uniprot entity ACADV_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7224663-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1699C>T	p.Arg567Trp	missense_variant	18/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1699C>T	p.Arg567Trp	missense_variant	18/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 145926 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000372 AC: 5 AN: 1342862 Hom.: 0 Cov.: 39 AF XY: 0.00000452 AC XY: 3 AN XY: 663912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000324

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000383

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 145926 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70878

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 567 of the ACADVL protein (p.Arg567Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 28600779). This variant is also known as c.1633C>T:p.R545W. ClinVar contains an entry for this variant (Variation ID: 219172). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg567 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23480858; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Strand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd	-	Though the observed variant has not been reported in a clinical context, an overlapping known missense variant, p.Arg567Gln was found to be associated with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) and was suggested to be present in the C-terminal region unique to ACADVL and ACAD9. In a cohort study consisting of 13 VLCADD patients, p.Arg567Gln variant was observed in a 6 years old male patient in a compound heterozygous state with p.Gly514Glu variant. Fatty acid oxidation probe assay in patient fibroblast reported elevated C14 , C12 and C16 levels but the patient was asymptomatic.The VLCAD activity assay and immunohistologic staining for VLCAD performed on patient fibroblasts reported that p.Arg567Gln variant caused loss of expression and exhibited partial activity as compared to wild type cells. Moreover, prokaryotic mutagenesis and expression studies done on E.coli revealed that p.Arg567Gln variant markedly decreased VLCAD antigen levels making it deleterious while p.Gly514Glu variant showed normal VLCAD antigen levels [PMID:23480858]. Thus, alteration of Arg-567 in both copies of the gene is likely to play a role severe clinical manifestation. The novel variant Arg567Trp, has a probable but no proven role in the disease manifestation; thus it has been classified as a VUS with a likely role in the observed clinical indication. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	33
Dann	Uncertain	0.98
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.76	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.4	D;.;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.78
MutPred		0.80		.;Gain of catalytic residue at L565 (P = 0.0034);.;
MVP		0.99
MPC		0.78
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864321651; hg19: chr17-7127981; COSMIC: COSV50035625; COSMIC: COSV50035625;