chr17-7220662-TC-T

Variant names:

• chr17-7220662-TC-T
• rs771808680
• NM_000018.4:c.266delC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.266del variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 4/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The variant has been identified in at least one individual identified by abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency without an additional ACADVL variant identified or follow-up plasma acylcarnitines (PMID:26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005437 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 12/14/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337611/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADVL NM_000018.4 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: -0.557
• Publications: 0 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]

ACADVL Gene-Disease associations (from GenCC):

• very long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Specifications for ACADVL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000018.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.266delC	p.Pro89HisfsTer28	frameshift	Exon 4 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.335delC	p.Pro112HisfsTer28	frameshift	Exon 5 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.200delC	p.Pro67HisfsTer28	frameshift	Exon 3 of 19	NP_001029031.1	P49748-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.266delC	p.Pro89HisfsTer28	frameshift	Exon 4 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.200delC	p.Pro67HisfsTer28	frameshift	Exon 3 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.335delC	p.Pro112HisfsTer28	frameshift	Exon 5 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251470 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Very long chain acyl-CoA dehydrogenase deficiency (6)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.56
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs771808680;

hg19: chr17-7123981;