rs1443151475

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_SupportingPM3PVS1PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID:25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA624861220/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: -0.0620

Publications

6 publications found

Variant links:

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 links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

DLG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 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.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4 link	c.104delC	p.Pro35LeufsTer26	frameshift_variant	Exon 2 of 20	ENST00000356839.10	NP_000009.1	P49748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 link	c.104delC	p.Pro35LeufsTer26	frameshift_variant	Exon 2 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

137290

AF XY:

0.0000267

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.00000360

AC:

AN:

1388036

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

685150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32326

American (AMR)

AF:

0.0000280

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25076

East Asian (EAS)

AF:

0.00

AC:

AN:

36750

South Asian (SAS)

AF:

0.00

AC:

AN:

79834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4752

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

1081424

Other (OTH)

AF:

0.00

AC:

AN:

57924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:4

Nov 01, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NM_000018.3:c.104delC (NP_000009.1:p.Pro35LeufsTer26) [GRCH38: NC_000017.11:g.7220163delC] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 25834949 . This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -

May 06, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ACADVL c.104delC (p.Pro35LeufsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.2e-05 in 137290 control chromosomes. c.104delC has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1999, Knottnerus_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports that enzyme activity in the patient carrying homozygous c.104delC had <10% of normal activity (Knottnerus_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 06, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID: 25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021). -

Dec 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Pro35Leufs*26) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 25834949). ClinVar contains an entry for this variant (Variation ID: 541718). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.062

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over