rs533055438

chr17-7223859-G-Achr17-7223859-G-Cchr17-7223859-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000018.4(ACADVL):c.1316G>A(p.Gly439Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,614,086 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G439A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 6.77

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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr17-7223859-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1484294.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 17-7223859-G-A is Pathogenic according to our data. Variant chr17-7223859-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 203582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1316G>A	p.Gly439Asp	missense_variant	13/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1316G>A	p.Gly439Asp	missense_variant	13/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251404 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461818 Hom.: 0 Cov.: 33 AF XY: 0.0000385 AC XY: 28 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000574 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.1316G>A (NP_000009.1:p.Gly439Asp) [GRCH38: NC_000017.11:g.7223859G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 439 of the ACADVL protein (p.Gly439Asp). This variant is present in population databases (rs533055438, gnomAD 0.005%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 17999356, 23480858; Invitae). ClinVar contains an entry for this variant (Variation ID: 203582). 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.Gly439 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 13, 2023	- -

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Expression of G439D in E. coli found no detectable enzyme activity compared to wild-type controls (Schiff et al., 2013); This variant is associated with the following publications: (PMID: 30925787, 23169530, 27209629, 17999356, 23480858, 30194637, 31031081, 20060901) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2018	The ACADVL c.1316G>A; p.Gly439Asp variant (rs533055438) is reported in the literature in individuals diagnosed with VLCAD deficiency, who are heterozygous for another ACADVL variant (Gobin-Limballe 2010, Pena 2016, Schiff 2013). Cultured fibroblasts from an individual carrying p.Gly439Asp and p.Met443Arg, showed no detectable VLCAD activity (Schiff 2013). Furthermore, functional analysis of p.Gly439Asp expressed using an in vitro prokaryotic system yielded no activity, even though protein of the correct size was detected by Western blot (Schiff 2013). The p.Gly439Asp variant is reported as pathogenic in ClinVar (Variation ID: 203582), and found in the general population with a low frequency of 0.002% (6/277134 alleles) in the Genome Aggregation Database. The glycine at codon 439 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Based on the above information, this variant is considered pathogenic. REFERENCES Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.8	D;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.97
MVP		0.99
MPC		0.87
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs533055438; hg19: chr17-7127178;