rs1085307648

chr17-7224711-C-Gchr17-7224711-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000018.4(ACADVL):c.1748C>G(p.Ser583Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000554 in 1,444,792 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S583L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 4.72

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 9 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 chr17-7224711-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 550315.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 17-7224711-C-G is Pathogenic according to our data. Variant chr17-7224711-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426482.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1748C>G	p.Ser583Trp	missense_variant	18/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1748C>G	p.Ser583Trp	missense_variant	18/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1444792 Hom.: 0 Cov.: 36 AF XY: 0.00000557 AC XY: 4 AN XY: 717598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000634

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000566 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2022	Variant summary: ACADVL c.1748C>G (p.Ser583Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 224028 control chromosomes (gnomAD). c.1748C>G has been reported in the literature in at least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and in individuals identified through newborn screening (Souri_1998, Olsen_2010, Miller_2015, Hesse_2018). Experimental evidence demonstrated the variant affects protein function (Souri_1998). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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.1748C>G (NP_000009.1:p.Ser583Trp) [GRCH38: NC_000017.11:g.7224711C>G] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9599005 . This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 583 of the ACADVL protein (p.Ser583Trp). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 9599005, 20480395, 26385305). ClinVar contains an entry for this variant (Variation ID: 426482). 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. Experimental studies have shown that this missense change affects ACADVL function (PMID: 9599005). This variant disrupts the p.Ser583 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15210884, 16464760, 23774949). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 03, 2022	- -

ACADVL-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2023

The ACADVL c.1748C>G variant is predicted to result in the amino acid substitution p.Ser583Trp. This variant was reported in individuals with very long chain acyl-CoA dehydrogenase deficiency, though a second variant was not identified in any of these reports (Hesse et al. 2018. PubMed ID: 30194637; Supplementary Table S2, Miller et al. 2015. PubMed ID: 26385305; Souri et al. 1998. PubMed ID: 9599005). In vitro models demonstrate that this variant disrupts ACADVL protein association with the inner mitochondrial membrane and dimer assembly (Souri et al. 1998. PubMed ID: 9599005). Residual ACADVL enzyme activity was reported to be only 28% of wild type in an individual heterozygous for the c.1748C>G change, further suggesting a loss of function mechanism (Hesse et al. 2018. PubMed ID: 30194637). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7128030-C-G). This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 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; This variant is associated with the following publications: (PMID: 8554073, 26385305, 9599005, 30194637) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	29
Dann	Benign	0.93
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.9	D;.;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.79
MutPred		0.51		.;Loss of disorder (P = 0.0028);.;
MVP		0.98
MPC		0.91
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307648; hg19: chr17-7128030;