rs375284481

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM2_SupportingPP4_ModeratePM3

This summary comes from the ClinGen Evidence Repository: The c.481G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 161 (p.Ala161Thr) and is also known as Ala121Thr by traditional nomenclature. The variant has been described in at least three individuals who displayed increased C14:1 acylcarnitines, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 28755359, 26385305, 16488171). In at least one of these individuals, the variant was confirmed as occurring in trans to a variant the ACADVL VCEP has classified as likely pathogenic and not confirmed in trans to a variant the ACADVL VCEP has classified as pathogenic (PM3, 1.5 points, PMID:16488171, 16950999). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001975 in Admixed American 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 0.773, 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: PP4_Moderate, PM3, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337740/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 7.03

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.481G>A	p.Ala161Thr	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.481G>A	p.Ala161Thr	missense_variant	7/20	1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251452

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:3Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 161 of the ACADVL protein (p.Ala161Thr). This variant is present in population databases (rs375284481, gnomAD 0.02%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 16488171, 16950999; Invitae). This variant is also known as A121V. ClinVar contains an entry for this variant (Variation ID: 324987). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_000018.3(ACADVL):c.481G>A(A161T) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. A161T has been observed in cases with relevant disease (PMID: 16488171, 16950999, 20480395). Functional assessments of this variant are not available in the literature. A161T has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.481G>A(A161T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ACADVL c.481G>A (p.Ala161Thr) variant has been reported in one study in a compound heterozygous state with another missense variant in one individual with very long-chain-acyl-CoA dehydrogenase (VLCAD) deficiency (Boneh et al. 2006). The variant was also identified in a heterozygous state in the unaffected father. Control data are unavailable for this variant which is reported at a frequency of 0.00017 in the total population of the Exome Aggregation Consortium. The Ala161 residue is conserved. The evidence for this variant is limited. The p.Ala161Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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.481G>A (NP_000009.1:p.Ala161Thr) [GRCH38: NC_000017.11:g.7221541G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 16488171. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 15, 2022	- -

ACADVL-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2024

The ACADVL c.481G>A variant is predicted to result in the amino acid substitution p.Ala161Thr. This variant has been reported in the compound heterozygous state in an individual with very long chain acyl-CoA dehydrogenase deficiency (Boneh et al. 2006. PubMed ID: 16488171). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2024

Identified in an individual with hypertrophic cardiomyopathy who was also found to harbor a pathogenic variant in MYH7 (PMID: 37498360); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27246109, 16950999, 16488171, 28755359, 26385305, 20480395, 37498360) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;D;.;.;D

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.4

D;.;.;D;.

REVEL

Pathogenic

0.77

Sift

Benign

0.057

T;.;.;D;.

Sift4G

Benign

0.13

T;T;D;T;D

Polyphen

1.0, 1.0

.;D;.;D;.

Vest4

0.85

MVP

0.97

MPC

0.30

ClinPred

0.50

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.69

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