rs750043368

Positions:

• chr17-7220626-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000018.4(ACADVL):​c.227G>A​(p.Gly76Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,890 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: 2.81

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• PP5: Variant 17-7220626-G-A is Pathogenic according to our data. Variant chr17-7220626-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554006.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.227G>A	p.Gly76Glu	missense_variant	4/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.227G>A	p.Gly76Glu	missense_variant	4/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251474 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 727246

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: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 06, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 14, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	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. . -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 17, 2021

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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.86	D;D;T;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	0.80	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N;.;.;N;.
REVEL	Pathogenic	0.65
Sift	Benign	0.37	T;.;.;T;.
Sift4G	Benign	0.35	T;T;T;T;D
Polyphen		0.99, 0.14	.;D;.;B;.
Vest4		0.57
MutPred		0.77		.;Gain of disorder (P = 0.0576);Gain of disorder (P = 0.0576);.;Gain of disorder (P = 0.0576);
MVP		0.94
MPC		0.87
ClinPred		0.76	D
GERP RS		4.9
Varity_R		0.51
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs750043368; hg19: chr17-7123945;