rs398123091

Variant names:

• chr17-7221993-G-A
• rs398123091
• NM_000018.4:c.664G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7221993-G-A
• chr17-7221993-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PM3_Supporting PM1 PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.664G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by arginine at amino acid 222 (p.Gly222Arg). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and a distinct variants not yet evaluated by the ACADVL VCEP, at least one individual was compound het for this variant and a variant determined by the ACADVL VCEP as likely pathogenic, and at least one individual was homozygous for the variant (PM3_Supporting, PMID:24801231, 20060901, 16443431, 28771436, 31844625). At least one patient with this variant displayed increased C14:1 levels and another patient showed significantly reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels, which is highly specific for VLCAD deficiency (PP4_moderate, PMID:24801231, PMID:20060901). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.981, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). This variant resides within a region, amino acids 214-223, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMID:9973285, 18227065, 20060901; PM1). 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_Supporting, PP3, PP4_moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA220218/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 6.69
• Publications: 16 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.664G>A	p.Gly222Arg	missense	Exon 8 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.733G>A	p.Gly245Arg	missense	Exon 9 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.598G>A	p.Gly200Arg	missense	Exon 7 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.664G>A	p.Gly222Arg	missense	Exon 8 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.598G>A	p.Gly200Arg	missense	Exon 7 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.733G>A	p.Gly245Arg	missense	Exon 9 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251384 AF XY: 0.00000736

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: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74274

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

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

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

Alfa AF: 0.0000177 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Very long chain acyl-CoA dehydrogenase deficiency (9)
3	-	-	not provided (3)
1	-	-	ACADVL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Gain of glycosylation at P219 (P = 0.1033)
MVP		1.0
MPC		0.84
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 1

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

Other links and lift over

dbSNP: rs398123091; hg19: chr17-7125312;