rs398123091

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3_SupportingPP4_ModeratePM1PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.664G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by arginine at amino acid 222 (p.Gly222Arg). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and a distinct variants not yet evaluated by the ACADVL VCEP, at least one individual was compound het for this variant and a variant determined by the ACADVL VCEP as likely pathogenic, and at least one individual was homozygous for the variant (PM3_Supporting, PMID:24801231, 20060901, 16443431, 28771436, 31844625). At least one patient with this variant displayed increased C14:1 levels and another patient showed significantly reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels, which is highly specific for VLCAD deficiency (PP4_moderate, PMID:24801231, PMID:20060901). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the 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 0.981, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). This variant resides within a region, amino acids 214-223, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMID:9973285, 18227065, 20060901; PM1). 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: PM1, PM2_supporting, PM3_Supporting, PP3, PP4_moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA220218/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 6.69

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 7 ACMG points.

PM1

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.

PP3

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.664G>A	p.Gly222Arg	missense_variant	Exon 8 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.664G>A	p.Gly222Arg	missense_variant	Exon 8 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

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:

0.0000119

AC:

AN:

251384

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

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:

0.0000508

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:9

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.664G>A (NP_000009.1:p.Gly222Arg) [GRCH38: NC_000017.11:g.7221993G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 20060901. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Dec 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2023

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.664G>A (p.Gly222Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251384 control chromosomes (gnomAD). c.664G>A has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Voermans_2006, Gobin-Limballe_2010, Li_2015, Miller_2015, Chen_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in decreased protein expression and approximately 10% of normal activity (e.g. Gobin-Limballe_2010). Furthermore, another variant resulting in the same amino acid change (c.664G>C, p.G222R) has also been classified as pathogenic/likely pathogenic in ClinVar and is reported in association with affected individuals in the HGMD database. The following publications have been ascertained in the context of this evaluation (PMID: 33150772, 20060901, 25652019, 26385305, 16443431). Seven submitters, including the ClinGen ACADVL Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 222 of the ACADVL protein (p.Gly222Arg). This variant is present in population databases (rs398123091, gnomAD 0.003%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 20060901, 25652019, 26182500). This variant is also known as G245R. ClinVar contains an entry for this variant (Variation ID: 92289). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Dec 14, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2023

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.664G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by arginine at amino acid 222 (p.Gly222Arg). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and a distinct variants not yet evaluated by the ACADVL VCEP, at least one individual was compound het for this variant and a variant determined by the ACADVL VCEP as likely pathogenic, and at least one individual was homozygous for the variant (PM3_Supporting, PMID: 24801231, 20060901, 16443431, 28771436, 31844625). At least one patient with this variant displayed increased C14:1 levels and another patient showed significantly reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 24801231, PMID: 20060901). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the 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 0.981, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). This variant resides within a region, amino acids 214-223, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285, 18227065, 20060901; PM1). 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: PM1, PM2_supporting, PM3_Supporting, PP3, PP4_moderate -

Aug 21, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.664G>A; p.Gly222Arg variant (rs398123091) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) (Gobin-Limballe 2010, Voermans 2006). This variant is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 92289), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 222 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this nucleotide position (c.664G>C; p.Gly222Arg) has been reported in individuals with VLCADD (Zhang 2014). Glycine 222 is part of a conserved GSD segment critical for cofactor binding, and p.G222R is predicted to disrupt this interaction (Gobin-Limballe 2010). Furthermore, in vitro functional analyses demonstrate reduced ACADVL protein levels (Gobin-Limballe 2010). Based on available information, the c.664G>A; p.Gly222Arg variant is considered to be pathogenic. References: Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. Voermans NC et al. Rhabdomyolysis caused by an inherited metabolic disease: very long-chain acyl-CoA dehydrogenase deficiency. Am J Med. 2006 Feb;119(2):176-9. Zhang RN et al. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr. 2014 May;10(2):119-25. -

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Sep 16, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16443431, 20060901, 25652019, 24801231, 32820518, 27535533, 17999356, 28991257, 26182500, 21378393, 24898617) -

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACADVL-related disorder

Pathogenic:1

Aug 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADVL c.664G>A variant is predicted to result in the amino acid substitution p.Gly222Arg. This variant has been reported in the homozygous state or along with a second ACADVL variant in individuals with very long chain acyl-CoA dehydrogenase deficiency (VLCADD). At least one of these individuals was reported to present with mild clinical features (Gobin-Limballe et al. 2010. PubMed ID: 20060901; Voermans et al. 2006. PubMed ID: 16443431; Bastin et al. 2011. PubMed ID: 21378393; Li et al. 2015. PubMed ID: 25652019). Analyses of fibroblast cells from a patient homozygous for the c.664G>A (p.Gly222Arg) substitution showed greatly reduced fatty acid oxidation and ACADVL protein levels (Gobin-Limballe et al. 2010. PubMed ID: 20060901). A different nucleotide substitution resulting in the same amino acid substitution (c.664G>C, p.Gly222Arg) has also been reported in association with VLCADD (Zhang et al. 2014. PubMed ID: 24801231; Li et al. 2015. PubMed ID: 25652019). In ClinVar this variant is interpreted as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/92289/). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;D;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.7

.;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.7

D;.;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.012

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.99

MutPred

0.99

.;Gain of glycosylation at P219 (P = 0.1033);.;

MVP

1.0

MPC

0.84

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.39

Position offset: 1

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