rs113994167

Variant names:

• chr17-7222272-T-C
• rs113994167
• NM_000018.4:c.848T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM3_Strong PM1 PS3_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.848T>C variant in ACADVL is a missense variant predicted to cause substitution of valine by alanine at amino acid 283 (p.Val283Ala). This variant is also known as Val243Ala when numbered from the mature peptide. The variant accounts for up to 29% of individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency identified by newborn screen (PMID:20301763). This variant has been reported in at least 12 individuals with VLCAD in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4_moderate; PMID:17999356, 26385305, 20107901, 14517516). The variant was detected at least 9 times in the homozygous state as well as at least 1 confirmed in-trans with another pathogenic variant (PM3_Strong; PMID:20107901; 17999356, 17999356). In vitro expression showed 20-25% residual enzyme activity when expressed in COS7 cells (PS3_supporting; PMID:9973285). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002238 in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The variant is located in a well-studied outer loop with structural importance with high homology to medium-chain acyl-CoA dehydrogenase (PM1; PMID:14517516). The computational predictor REVEL gives a score of 0.905, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3_Strong, PM1, PP3, PS3_supporting (ACADVL specifications version 1; approved November 8, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA285294/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:33 O:3
• Conservation: PhyloP100: 6.70
• Publications: 60 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

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.848T>C	p.Val283Ala	missense	Exon 9 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.917T>C	p.Val306Ala	missense	Exon 10 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.782T>C	p.Val261Ala	missense	Exon 8 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.848T>C	p.Val283Ala	missense	Exon 9 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.782T>C	p.Val261Ala	missense	Exon 8 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.917T>C	p.Val306Ala	missense	Exon 10 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00126 AC: 318 AN: 251396 AF XY: 0.00138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00165 AC: 2406 AN: 1461826 Hom.: 4 Cov.: 32 AF XY: 0.00167 AC XY: 1217 AN XY: 727218

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26134

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53372

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

European-Non Finnish (NFE) AF: 0.00197 AC: 2194 AN: 1112000

Other (OTH) AF: 0.00182 AC: 110 AN: 60390

GnomAD4 genome AF: 0.00109 AC: 166 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.000956 AC XY: 71 AN XY: 74236

African (AFR) AF: 0.000242 AC: 10 AN: 41368

American (AMR) AF: 0.00124 AC: 19 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00162 Hom.: 2

Bravo AF: 0.00113

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00143 AC: 173

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
21	-	-	Very long chain acyl-CoA dehydrogenase deficiency (23)
8	-	-	not provided (9)
1	-	-	ACADVL-related disorder (1)
1	-	-	Acute rhabdomyolysis (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.31	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.5	L
PhyloP100		6.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.60	P
Vest4		0.91
MVP		0.96
MPC		0.59
ClinPred		0.077	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.70
Mutation Taster		=28/72	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

Other links and lift over

dbSNP: rs113994167; hg19: chr17-7125591;