rs1057517281

Variant names:

• chr17-7223193-CAGG-C
• rs1057517281
• NM_000018.4:c.1141_1143delGAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PM3_Strong PM4 PM1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1141_1143delGAG variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu381del) (PM4). The variant is reported in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency (PMID:25834949, 24305961, 21814341, 8845838). Six individuals were reported to have both elevated C14:1 levels and reduced VLCAD enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8845838, 21814341, 24305961, 25834949, 31031081). Of these individuals, one individual was homozygous for this variant, at least two of the individuals also carried an additional pathogenic variant not confirmed in trans, and at least four confirmed in trans to variants not yet curated by the VCEP (PM3; PMID:24305961, 25834949, 32276429). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within a region of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID:20060901). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_supporting, PM3, PM4, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041870/MONDO:0008723/021

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACADVL NM_000018.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.78
• Publications: 5 publications found

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]

MIR324 (HGNC:31767): (microRNA 324) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1141_1143delGAG	p.Glu381del	conservative_inframe_deletion	Exon 11 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1141_1143delGAG	p.Glu381del	conservative_inframe_deletion	Exon 11 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6

Feb 12, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADVL c.1141_1143delGAG (p.Glu381del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251488 control chromosomes (gnomAD). c.1141_1143delGAG has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (examples: Andresen_1996, Pervaiz_2011, Diekman_2016, Rovelli_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8845838, 26881790, 21814341, 31031081). ClinVar contains an entry for this variant (Variation ID: 371449). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 09, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1141_1143delGAG variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu381del) (PM4). The variant is reported in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency (PMID: 25834949, 24305961, 21814341, 8845838). Six individuals were reported to have both elevated C14:1 levels and reduced VLCAD enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8845838, 21814341, 24305961, 25834949, 31031081). Of these individuals, one individual was homozygous for this variant, at least two of the individuals also carried an additional pathogenic variant not confirmed in trans, and at least four confirmed in trans to variants not yet curated by the VCEP (PM3; PMID: 24305961, 25834949, 32276429). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within a region of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_supporting, PM3, PM4, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). -

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1141_1143del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Glu381del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8845838, 21814341, 31031081). ClinVar contains an entry for this variant (Variation ID: 371449). Studies have shown that this variant alters ACADVL gene expression (PMID: 8845838). For these reasons, this variant has been classified as Pathogenic. -

Jan 05, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057517281; hg19: chr17-7126512;