chr17-7221613-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2_SupportingPM3PP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The c.553G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by serine at amino acid 185 (p.Gly185Ser). This variant has been detected in at least 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and distinct pathogenic variants (PM3, PMIDs: 31620161, 17999356).Two patients with this variant displayed beta Oxidation Flux <20% of normal and at least one individual showed increased acylcarnitines, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMIDs: 17999356, 31620161, 22841441). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in East 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 0.971, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). 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: PM3, PP4_moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA312291/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 8.86

Publications

12 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 Gene-Disease associations (from GenCC):

very long chain acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 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.

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.553G>A	p.Gly185Ser	missense_variant	Exon 7 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.553G>A	p.Gly185Ser	missense_variant	Exon 7 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251456

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000189

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:10

Aug 30, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM1, PP3, PS3, PP5, PM5 -

Dec 23, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACADVL c.553G>A, p.Gly185Ser variant (rs545215807), also known as Gly145Ser, has been reported in multiple individuals with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen 1999, Gobin-Limballe 2007, Yamaguchi 2012). Multiple affected individuals with this variant were also found to carry a second pathogenic variant (Gobin-Limballe 2007, Yamaguchi 2012). The p.Gly185Ser variant is listed in ClinVar (Variation ID: 203595) and is observed on only three chromosomes in the Genome Aggregation Database (3/251456 alleles). The glycine at position 185 is highly conserved (Alamut v2.10), and it occurs in the substrate binding cavity of the VLCAD enzyme (Hoffman 2012). Functional characterization of patient fibroblasts carrying this variant indicates a substantial decrease in VLCAD protein levels (Andresen 1999, Gobin-Limballe 2010) and enzymatic activity compared to wildtype (Gobin-Limballe 2007, Hoffman 2012). Based on available information, the p.Gly185Ser variant is considered to be pathogenic. References: Andresen B et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999; 64(2):479-94. Gobin-Limballe S et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007; 81(6):1133-43. 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; 1802(5):478-84. Hoffman L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2):269-77. Yamaguchi S et al. Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. Mol Genet Metab. 2012; 107(1-2):87-91. -

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.553G>A (NP_000009.1:p.Gly185Ser) [GRCH38: NC_000017.11:g.7221613G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Feb 23, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000203595). A different missense change at the same codon (p.Gly185Ala) has been reported to be associated with ACADVL related disorder (ClinVar ID: VCV000450792). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 29, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2021

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000018.3(ACADVL):c.553G>A(G185S) is a missense variant classified as likely pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. G185S has been observed in cases with relevant disease (PMID: 31620161, 32655480, 22841441, 21932095, 17999356, 9973285). Functional assessments of this variant are not available in the literature. G185S has been observed in population frequency databases (gnomAD: EAS 0.006%). In summary, NM_000018.3(ACADVL):c.553G>A(G185S) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Dec 14, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.553G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by serine at amino acid 185 (p.Gly185Ser). This variant has been detected in at least 4 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, two were compound heterozygous for the variant and distinct pathogenic variants (PM3, PMIDs: 31620161, 17999356). Two patients with this variant displayed beta Oxidation Flux <20% of normal and at least one individual showed increased acylcarnitines, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMIDs: 17999356, 31620161, 22841441). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in East 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 0.971, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). 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: PM3, PP4_moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). -

Dec 06, 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 serine, which is neutral and polar, at codon 185 of the ACADVL protein (p.Gly185Ser). This variant is present in population databases (rs545215807, gnomAD 0.006%). This missense change has been observed in individual(s) with diminished VLCAD protein expression and enzyme activity (PMID: 17999356, 20060901). ClinVar contains an entry for this variant (Variation ID: 203595). 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%. For these reasons, this variant has been classified as Pathogenic. -

Mar 08, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G145S); This variant is associated with the following publications: (PMID: 31589614, 21932095, 20060901, 9973285, 32655480, 32447334, 32778825, 17999356, 37308883, 18977676, 30925787, 31620161, 39375714, 22841441, 31844625, 29618732, 35400565, 39188284) -

Aug 09, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP4_moderate, PM2, PM3 -

ACADVL-related disorder

Pathogenic:1

May 12, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACADVL c.553G>A variant is predicted to result in the amino acid substitution p.Gly185Ser. This variant has been reported, along with a second ACADVL variant, in patients with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) ranging from the severe neonatal onset form to later onset exercise-induced rhabdomyolysis (Gobin-Limballe et al. 2007. PubMed ID: 17999356; Yamaguchi et al. 2012. PubMed ID: 22841441; Musumeci et al. 2020. PubMed ID: 32655480). It was also reported in the heterozygous state without a second ACADVL variant in a patient with 29% residual enzyme activity (Hoffmann et al. 2012. PubMed ID: 21932095, described as p.G145S). In fibroblasts from patients carrying the p.Gly185Ser substitution along with a second ACADVL variant, enzyme activity and protein levels were greatly reduced (Gobin-Limballe et al. 2007. PubMed ID: 17999356; Gobin-Limballe et al. 2010. PubMed ID: 20060901). Based on structure mapping, the p.Gly185 amino acid is predicted to lie in a very hydrophobic pocket lining the enzyme acyl-CoA binding cavity, and it has been noted that substitution of glycine with a polar serine residue in this location could affect substrate binding (Gobin-Limballe et al. 2010. PubMed ID: 20060901). This variant has been interpreted as likely pathogenic by the ClinGen ACADVL Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/203595/). Taken together, we interpret the c.553G>A (p.Gly185Ser) variant as likely pathogenic for autosomal recessive VLCADD. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;D;.;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

.;M;.;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.0

D;.;.;D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;T;D;T

Polyphen

1.0

.;D;.;D;.

Vest4

0.98

MVP

0.99

MPC

0.76

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.89

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over