rs113994171

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_SupportingPM3_StrongPS3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1679-6G>A variant in ACADVL is an intronic variant which creates a novel acceptor site in intron 17, experimentally shown to cause insertion of four nucleotides and causes a frameshift (PS3_Supporting; PMID:9709714). This variant has been reported in several individuals affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency confirmed in trans to at least one pathogenic variant, presumed in trans to distinct ACADVL variants, and in the homozygous state in at least two individuals (PM3_Strong; PMIDs:23480858, 9709714, 8845838). Fibroblasts derived from one of these individuals showed no detectable VLCAD activity, which is highly specific for VLCAD deficiency (PP4_Moderate; PMID:234808). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002264 in the Latino/Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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: PS3_Supporting, PM3_Strong, PM2_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA312281/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.8467

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 0.212

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS3

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/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1679-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1679-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

15944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000828

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000217

AC:

AN:

92036

Hom.:

AF XY:

0.0000396

AC XY:

AN XY:

50540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000226

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000746

AC:

AN:

388802

Hom.:

Cov.:

AF XY:

0.0000828

AC XY:

AN XY:

193228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000892

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000626

AC:

AN:

15978

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

8226

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000825

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000358

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change falls in intron 17 of the ACADVL gene. It does not directly change the encoded amino acid sequence of the ACADVL protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9709714, 9973285, 23480858). ClinVar contains an entry for this variant (Variation ID: 21019). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.1679-6G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7224636G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9709714. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 06, 2020	Variant summary: ACADVL c.1679-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. One predicts the variant abolishes a 3' acceptor site and another that it weakens a 3' acceptor site. Experimental evidence also suggests that this variant affects normal mRNA splicing (Cox_1998, Andresen_1999). The variant allele was found at a frequency of 2.2e-05 in 92036 control chromosomes (gnomAD). c.1679-6G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Cox_1998, Andresen_1999, Schiff_2013). VLCAD enzymatic activity was not detected from patient's fibroblasts samples who harbored this variant and another pathogenic variant (Schiff_2013).These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 19, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 02, 2020	The ACADVL c.1679-6G>A variant (rs113994171) is reported in the literature in multiple individuals affected with VLCAD deficiency, both in homozygous and compound heterozygous individuals (Andresen 1996, Andresen 1999, Cox 1998, Schiff 2013). This variant is found on only two chromosomes in the Genome Aggregation Database (2/92036 alleles), indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Consistent with these predictions, analyses of mRNAs from individuals with this variant indicate decreased mRNA levels and insertion of four nucleotides due to usage of the cryptic splice acceptor (Andresen 1996, Cox 1998). Based on available information, this variant is considered to be pathogenic. References: Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996 Apr;5(4):461-72. Cox GF et al. Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 1998 Aug;133(2):247-53. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 29, 2015	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Dec 14, 2022	The c.1679-6G>A variant in ACADVL is an intronic variant which creates a novel acceptor site in intron 17, experimentally shown to cause insertion of four nucleotides and causes a frameshift (PS3_Supporting; PMID: 9709714). This variant has been reported in several individuals affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency confirmed in trans to at least one pathogenic variant, presumed in trans to distinct ACADVL variants, and in the homozygous state in at least two individuals (PM3_Strong; PMIDs:23480858, 9709714, 8845838). Fibroblasts derived from one of these individuals showed no detectable VLCAD activity, which is highly specific for VLCAD deficiency (PP4_Moderate; PMID: 234808). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002264 in the Latino/Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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: PS3_Supporting, PM3_Strong, PM2_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). -

ACADVL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2023

The ACADVL c.1679-6G>A variant is predicted to interfere with splicing. This variant has been reported in the apparent homozygous state or heterozygous state with a known pathogenic variant in patients with enzymatically confirmed very long chain acyl-CoA dehydrogenase deficiency (VLCADD) (described as Ins4bp-1679 in Andresen et al. 1996. PubMed ID: 8845838; Figure 2 in Cox et al. 1998. PubMed ID: 9709714; Schiff et al. 2013. PubMed ID: 23480858). It has also been reported on five alleles from four patients with clinically suspected VLCADD (described as -6G-->A in intron 17 in Andresen et al. 1999. PubMed ID: 9973285). Available splicing prediction programs suggest that this variant would weaken the nearby canonical splice acceptor site and create a novel splice acceptor site 4 nucleotides upstream (Alamut Visual v2.11). Consistent with this prediction, based on cDNA analysis this variant was confirmed to lead to aberrant splicing and the insertion of an additional 4 nucleotides, predicted to lead to a frameshift and premature protein termination. Additionally, this variant has been reported to lead to decreased mRNA level (Andresen et al. 1996. PubMed ID: 8845838; Cox et al. 1998. PubMed ID: 9709714). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7127955-G-A). Taken together, this variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2023

This variant was found to result in abnormal splicing resulting in a frameshift variant in a gene for which loss of function is a known mechanism of disease (Cox GF et al., 1998); This variant is associated with the following publications: (PMID: 23480858, 32870709, 9709714, 8845838) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Uncertain

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over