17-7224711-C-T

Variant names:

• chr17-7224711-C-T
• rs1085307648
• NM_000018.4:c.1748C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2_Supporting PM3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL): c.1748C>T (p.Ser583Leu) variant in ACADVL is a missense variant predicted to cause substitution of serine by leucine at amino acid 583 (p.Ser583Leu). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, both were homozygous for the variant; Moreover, this variant was co-detected with c.848T>C (p.Val283Ala) variant with unknown phase (PM3 point 1.5, PMIDs 32518924, 23774949) (PM3). At least two patients with this variant in homozygous state displayed clinical phonotypes, NBS abnormalities and/or increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Supporting, PMIDs 32518924). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID:26385305).The highest population minor allele frequency in gnomAD v2.1.1 is 0.000034 in 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 0.674, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limited evidence, this variant is classified as a variant of uncertain significance 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: PM3, PM2_Supporting, PP4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA397725788/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.72
• 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]

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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.1748C>T	p.Ser583Leu	missense	Exon 18 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1817C>T	p.Ser606Leu	missense	Exon 19 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1682C>T	p.Ser561Leu	missense	Exon 17 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.1748C>T	p.Ser583Leu	missense	Exon 18 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1682C>T	p.Ser561Leu	missense	Exon 17 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1817C>T	p.Ser606Leu	missense	Exon 19 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000893 AC: 2 AN: 224028 AF XY: 0.00000821

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: 0.00

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444792 Hom.: 0 Cov.: 36 AF XY: 0.00000557 AC XY: 4 AN XY: 717598

African (AFR) AF: 0.0000303 AC: 1 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 42274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 38734

South Asian (SAS) AF: 0.00 AC: 0 AN: 84552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103660

Other (OTH) AF: 0.0000336 AC: 2 AN: 59590

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	1	-	Very long chain acyl-CoA dehydrogenase deficiency (6)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.47		Loss of catalytic residue at S583 (P = 0.0169)
MVP		0.96
MPC		0.72
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.93
gMVP		0.87
Mutation Taster		=0/100	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: rs1085307648; hg19: chr17-7128030;