rs387906251

Variant names:

• chr17-7220964-TGGA-T
• rs387906251
• NM_000018.4:c.388_390delGAG

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000018.4(ACADVL):​c.388_390delGAG​(p.Glu130del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000773898: Studies have shown that this variant alters ACADVL gene expression (PMID:8554073)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E130E) has been classified as Likely benign. The gene ACADVL is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ACADVL NM_000018.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 8.70
• Publications: 2 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000773898: Studies have shown that this variant alters ACADVL gene expression (PMID: 8554073).; SCV001160512: "In vitro functional analyses demonstrate production of unstable transcripts and reduced enzyme activity (Souri 1996)."; SCV001362322: One paper reports this variant retain less than 10% of enzyme activity compared to WT (Souri_1996).; SCV001364888: This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3; SCV002576771: Assays, including mRNA/protein expression (in CHO cells), and enzymatic activity demonstrate unstable protein products indicating that this variant impacts protein function (PMID: 8554073 )(PS3).; SCV001830577: Functional studies found that the c.388_390del variant is associated with significantly reduced levels of VLCAD protein and reduced enzyme activity (PMID: 8554073);; SCV004118080: "In vitro functional characterization suggested that this variant is deleterious" (Souri et al. 1996. PubMed ID: 8554073).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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 17-7220964-TGGA-T is Pathogenic according to our data. Variant chr17-7220964-TGGA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1626.Status of the report is reviewed_by_expert_panel, 3 stars.

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.388_390delGAG	p.Glu130del	conservative_inframe_deletion	Exon 6 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.457_459delGAG	p.Glu153del	conservative_inframe_deletion	Exon 7 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.322_324delGAG	p.Glu108del	conservative_inframe_deletion	Exon 5 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.388_390delGAG	p.Glu130del	conservative_inframe_deletion	Exon 6 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.322_324delGAG	p.Glu108del	conservative_inframe_deletion	Exon 5 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.457_459delGAG	p.Glu153del	conservative_inframe_deletion	Exon 7 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152078 Hom.: 0 Cov.: 33

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: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251410 AF XY: 0.0000221

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 FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461816 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 727194

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: 39700

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

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53346

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

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

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Very long chain acyl-CoA dehydrogenase deficiency (10)
1	-	-	ACADVL-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=27/73	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs387906251;

hg19: chr17-7124283;