17-7223199-A-C

Position:

chr17-7223199-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PM2_SupportingPS3_SupportingPP4_ModeratePM3PM1

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL):c.1144A>C (p.Lys382Gln) variant in ACADVL is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 382. The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00005 in East Asian population (one allele), which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_ Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who was compound heterozygous for the variant and a pathogenic variant confirmed in trans by molecular subcloning (PM3, PMID:8554073). The reported patient with this variant displayed reduced enzyme activities, which is highly specific for the disorder (PP4_Moderate, PMID:7769092). VLCAD enzyme activity assay in CHO cells showed 19% activity with appropriate controls indicating that this variant impacts protein function (PS3_Supporting, PMID:8554073). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID:20060901). The computational predictor REVEL gives a score of 0.95, 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 very long chain acyl CoA dehydrogenase (VLCAD) deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PM3, PP3, PM2_Supporting, PS3_Supporting, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251906/MONDO:0008723/021

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

10

6

3

Clinical Significance

Likely pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 6.38

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 9 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

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/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1144A>C	p.Lys382Gln	missense_variant	11/20	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.1144A>C	p.Lys382Gln	missense_variant	11/20	1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152170

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:

0.000193

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:

0.00000398

AC:

1

AN:

251490

Hom.:

0

AF XY:

0.00000736

AC XY:

1

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

2

AN:

1461786

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152170

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2022	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 382 of the ACADVL protein (p.Lys382Gln). This variant is present in population databases (rs118204015, gnomAD 0.006%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACADVL function (PMID: 8554073). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1628). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8554073, 20060901, 29552494, 31497477). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Dec 15, 2022	The NM_000018.4(ACADVL):c.1144A>C (p.Lys382Gln) variant in ACADVL is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 382. The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00005 in East Asian population (one allele), which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_ Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who was compound heterozygous for the variant and a pathogenic variant confirmed in trans by molecular subcloning (PM3, PMID: 8554073). The reported patient with this variant displayed reduced enzyme activities, which is highly specific for the disorder (PP4_Moderate, PMID: 7769092). VLCAD enzyme activity assay in CHO cells showed 19% activity with appropriate controls indicating that this variant impacts protein function (PS3_Supporting, PMID: 8554073). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.95, 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 very long chain acyl CoA dehydrogenase (VLCAD) deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PM3, PP3, PM2_Supporting, PS3_Supporting, PP4_Moderate). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.38

D

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

27

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.92

.;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.97

D

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.56

D

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.6

.;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.58

T

PROVEAN

Uncertain

-3.9

D;.;D

REVEL

Pathogenic

0.96

Sift

Benign

0.034

D;.;D

Sift4G

Uncertain

0.041

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.97

MutPred

0.89

.;Loss of methylation at K382 (P = 0.055);.;

MVP

0.99

MPC

0.79

ClinPred

0.90

D

GERP RS

5.6

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.91

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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: rs118204015; hg19: chr17-7126518;