NM_000018.4:c.37C>T

Variant names:

• chr17-7220021-C-T
• rs63750670
• NM_000018.4:c.37C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PVS1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.37C>T (p.Gln13Ter) variant in ACADVL is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed VLCAD enzyme levels of <20% of normal, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 20060901, 17999356). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the 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: PVS1, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA287433650/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACADVL NM_000018.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 1.27
• Publications: 3 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]

DLG4 (HGNC:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DLG4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder 62

  Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 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.
• 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.37C>T	p.Gln13*	stop_gained	Exon 1 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001033859.3		c.37C>T	p.Gln13*	stop_gained	Exon 1 of 19	NP_001029031.1	P49748-2
	DLG4	NM_001321074.1		c.-1172G>A		5_prime_UTR	Exon 1 of 22	NP_001308003.1	B9EGL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.37C>T	p.Gln13*	stop_gained	Exon 1 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.37C>T	p.Gln13*	stop_gained	Exon 1 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000945302.1		c.37C>T	p.Gln13*	stop_gained	Exon 1 of 20	ENSP00000615361.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453078 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 722922

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 85762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110892

Other (OTH) AF: 0.00 AC: 0 AN: 60104

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Rhabdomyolysis;C4023591:Abnormal circulating enzyme concentration (1)
1	-	-	Very long chain acyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		1.3
Vest4		0.69
GERP RS		4.9
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		4.0
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs63750670; hg19: chr17-7123340;