rs796051913

chr17-7222250-AAGG-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000018.4(ACADVL):c.829_831del(p.Glu277del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K276K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: ACADVL NM_000018.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:2
• Conservation: PhyloP100: 8.38

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000018.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-7222250-AAGG-A is Pathogenic according to our data. Variant chr17-7222250-AAGG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203589.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.829_831del	p.Glu277del	inframe_deletion	9/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.829_831del	p.Glu277del	inframe_deletion	9/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251448 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135912

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000322 AC: 470 AN: 1461854 Hom.: 0 AF XY: 0.000322 AC XY: 234 AN XY: 727232

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000379

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74316

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000170

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:10 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Uncertain significance, flagged submission	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000018.3(ACADVL):c.829_831delGAG(E277del) is an in-frame deletion classified as likely pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. E277del has been observed in cases with relevant disease (PMID: 27209629, 30194637, 32518924, 26385305, 23430948). Functional assessments of this variant are not available in the literature. E277del has been observed in population frequency databases (gnomAD: NFE 0.03%). In summary, NM_000018.3(ACADVL):c.829_831delGAG(E277del) is an in-frame deletion variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, flagged submission	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.829_831delGAG (NP_000009.1:p.Glu277del) [GRCH38: NC_000017.11:g.7222253_7222255del] 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2021	Variant summary: ACADVL c.829_831delGAG (p.Glu277del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.00017 in 251448 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00017 vs 0.0029), allowing no conclusion about variant significance. c.829_831delGAG has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Spiekerkoetter_2012, Alhashem_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and two (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 20, 2023	The ACADVL c.829_831delGAG; p.Glu277del (rs796051913), also known as Glu237del, has been detected in individuals affected with Very Long-Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) deficiency and is described as a recurrent variant in positive newborn screening for VLCAD deficiency (Hesse 2018, Miller 2015, Pena 2016, Spiekerkoetter 2012). It is reported in ClinVar (Variation ID: 203589) and is observed in the general population at an overall frequency of 0.02% (46/277204 alleles) in the Genome Aggregation Database. This variant deletes a single glutamic acid residue leaving the rest of the protein in-frame. Additionally, other single amino acid deletions (Glu130del, Glu297del, Lys299del) have been reported in association with VLCAD deficiency (Brown 2014, Miller 2015, Pena 2016). Based on above information, this variant is considered likely pathogenic. References: Brown A et al. Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Mol Genet Metab. 2014 Dec;113(4):278-82. PMID: 25456746. Hesse J et al. The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). J Inherit Metab Dis. 2018 Nov;41(6):1169-1178. PMID: 30194637. Isackson P et al. Novel mutations in the gene encoding very long-chain acyl-CoA dehydrogenase identified in patients with partial carnitine palmitoyltransferase II deficiency. Muscle Nerve. 2013 Feb;47(2):224-9. PMID: 23169530. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. 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. PMID: 27209629. Spiekerkoetter U et al. Lethal Undiagnosed Very Long-Chain Acyl-CoA Dehydrogenase Deficiency with Mild C14-Acylcarnitine Abnormalities on Newborn Screening. JIMD Rep. 2012;6:113-5. PMID: 23430948. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Glu277del variant in ACADVL (also referred to as c.829_831delGAG in the literature) has been reported in six individuals with biochemical features of very long-chain acyl-CoA dehydrogenase deficiency including five compound heterozygotes (Pena 2016 PMID: 27209629, Adhikari 2020 PMID: 32778825, Knottnerus 2020 PMID: 32061778, Spiekerkoetter 2012 PMID: 23430948, Hesse 2018 PMID: 30194637). It has also been identified in 0.041% (28/68022) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 203589). This variant is a deletion of one amino acid at position 277 and is not predicted to alter the protein reading-frame. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Knottnerus 2020 PMID: 32061778, Spiekerkoetter 2012 PMID: 23430948); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive very long-chain acyl-CoA dehydrogenase deficiency. ACMG/AMP criteria applied with specifications by the ACADVL VCEP Expert Panel: PM3_Strong, PP4_Moderate, PM2_Supporting, PM4_Supporting, PP3, PS3_Moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This variant, c.829_831del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu277del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs149680575, gnomAD 0.03%). This variant has been observed in individual(s) with VLCAD deficiency (PMID: 23169530, 23430948, 27209629, 30194637). ClinVar contains an entry for this variant (Variation ID: 203589). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 18, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2022	In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32778825, 20547398, 23169530, 30194637, 27209629, 23430948, 32061778) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -

ACADVL-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

The ACADVL c.829_831delGAG variant is predicted to result in an in-frame deletion (p.Glu277del). This variant was previously reported to be associated with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) and was observed in the compound heterozygous state in multiple patients (e.g., Spiekerkoetter et al. 2012. PubMed ID: 23430948; Yavarna et al. 2015. PubMed ID: 26077850; Pena et al. 2016. PubMed ID: 27209629; Knottnerus et al. 2020. PubMed ID: 32061778). Additionally, a similar variant involving an adjacent amino acid (c.833_835del; p.Lys278del) has also been observed in patients with VLCADD (Andresen et al. 1999. PubMed ID: 9973285; referred to as del830_32, delK238). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7125569-AAGG-A). Based on the collective evidence, the ACADVL c.829_831del variant is classified as likely pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

The c.829_831delGAG (p.E277del) alteration, located in coding exon 9 of the ACADVL gene, results from an in-frame GAG deletion at nucleotide positions 829 to 831. This results in the deletion of a glutamic acid residue at codon 277. Based on data from gnomAD, this allele has an overall frequency of 0.02% (47/282832) total alleles studied. The highest observed frequency was 0.04% (3/7226) of Other alleles. This alteration has been detected as compound heterozygous in multiple individuals diagnosed with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Spiekerkoetter, 2012; Pena, 2016; Hesse, 2018). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs796051913; hg19: chr17-7125569;