rs113994168

Positions:

chr17-7222203-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_ModeratePM2_SupportingPP3PM3PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL): c.779C>T (p.Thr260Met) variant is a missense variant predicted to cause substitution of threonine by methionine at amino acid 260. This variant has been detected in individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:8845838, 17374501, 32518924). This variant was found homozygous in two individuals with VLCAD deficiency (PM3, 1.0 point, PMIDs: 9327992, 32518924). Two enzyme activity assays in Cos-7 cells and E.coli showed residual enzyme activity between 3-5% of wildtype indicating that this variant impacts protein function (PMIDs: indicating that this variant impacts protein function (PMID:9973285, 9973285; PS3_supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European 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 0.875, 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: PM2_Supporting, PM3_moderate, PP3, PP4_Moderate, PS3_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA341526/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

11

6

2

Clinical Significance

Likely pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 4.96

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:

ACADVL (HGNC:):

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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.

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.779C>T	p.Thr260Met	missense_variant	9/20	ENST00000356839.10	NP_000009.1	P49748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.779C>T	p.Thr260Met	missense_variant	9/20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

7

AN:

152180

Hom.:

0

Cov.:

32

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

5

AN:

251458

Hom.:

0

AF XY:

0.0000221

AC XY:

3

AN XY:

135920

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:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000246

AC:

36

AN:

1461838

Hom.:

0

Cov.:

32

AF XY:

0.0000275

AC XY:

20

AN XY:

727226

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000460

AC:

7

AN:

152180

Hom.:

0

Cov.:

32

AF XY:

0.0000404

AC XY:

3

AN XY:

74332

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000495

Hom.:

0

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.0000165

AC:

2

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2018	Variant summary: ACADVL c.779C>T (p.Thr260Met) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain 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 2e-05 in 246264 control chromosomes (gnomAD). c.779C>T has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency as both a homozygous and compound heterozygous allele (Liebig_2006, Laforet_2009). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence showing a significant decrease (<10% of normal) in VLCAD activity in patient fibroblasts (Laforet_2009). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 260 of the ACADVL protein (p.Thr260Met). This variant is present in population databases (rs113994168, gnomAD 0.003%). This missense change has been observed in individual(s) with very-long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 19327992, 20060901, 21932095). ClinVar contains an entry for this variant (Variation ID: 21024). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 9973285, 17374501, 19327992). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	The ACADVL c.779C>T; p.Thr260Met variant (rs113994168), also known as Thr220Met, has been reported in multiple individuals diagnosed with very long chain acyl-CoA dehydrogenase deficiency, often found in-trans with another pathogenic variant (Andresen 1996, Andresen 1999, Gobin-Limballe 2010, Laforet 2009, Mathur 1999). Additionally, functional characterization of the variant protein in patient fibroblasts demonstrate significantly decreased enzymatic activity (Andresen 1996, Andresen 1999, Hoffman 2012, Laforet 2009). This variant is reported in ClinVar (Variation ID: 21024) and observed in the general population at a low overall frequency of 0.002% (5/246264 alleles) in the Genome Aggregation Database. The threonine at residue 260 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Based on available information, this variant is considered pathogenic. References: Andresen B 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; 5(4):461-72. PMID: 8845838. 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. PMID: 9973285. 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. PMID: 20060901. 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. PMID: 21932095. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009; 19(5):324-9. PMID: 19327992. Mathur A et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999; 99(10):1337-43. PMID: 10077518. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	May 16, 2024	The NM_000018.4(ACADVL): c.779C>T (p.Thr260Met) variant is a missense variant predicted to cause substitution of threonine by methionine at amino acid 260. This variant has been detected in individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 8845838, 17374501, 32518924). This variant was found homozygous in two individuals with VLCAD deficiency (PM3, 1.0 point, PMIDs: 9327992, 32518924). Two enzyme activity assays in Cos-7 cells and E.coli showed residual enzyme activity between 3-5% of wildtype indicating that this variant impacts protein function (PMIDs: indicating that this variant impacts protein function (PMID: 9973285, 9973285; PS3_supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European 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 0.875, 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: PM2_Supporting, PM3_moderate, PP3, PP4_Moderate, PS3_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021). -
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.779C>T (NP_000009.1:p.Thr260Met) [GRCH38: NC_000017.11:g.7222203C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8845838. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 16, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 04, 2021

ACMG categories: PS5,PM1,PM2,PM3,PP3,PP4,PP5,BP1 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2020

Published functional studies found T260M is associated with significantly reduced enzyme activity (Andresen et al., 1999; Goetzman et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20480395, 17374501, 25087612, 20060901, 9973285, 8845838, 21932095, 27943070, 30194637, 16950999, 20301763, 10077518, 19327992, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.42

D

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

27

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

.;D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

D

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.54

D

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

0.97

D

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Uncertain

0.64

T

PROVEAN

Pathogenic

-6.0

D;.;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.90

MVP

0.97

MPC

0.77

ClinPred

0.96

D

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Other links and lift over

dbSNP: rs113994168; hg19: chr17-7125522;