rs545215807

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPM3PP3PP4_Moderate

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
ENST00000356839.10 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 8.86

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 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/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.553G>A	p.Gly185Ser	missense_variant	7/20	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.553G>A	p.Gly185Ser	missense_variant	7/20	1	NM_000018.4	ENSP00000349297	P1	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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251456

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135918

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000385

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

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

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -
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.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 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Dec 14, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2021	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 09, 2023	PP3, PP4_moderate, PM2, PM3 -

ACADVL-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2023

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

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;.;.;.

MutationTaster

Benign

1.0

D;D;D

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

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

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