17-7222242-G-C

Position:

chr17-7222242-G-C

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 3P and 4B. PM3_SupportingBS1PP3PP4

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala) in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 273 (p. Gly273Ala). The highest population minor allele frequency in gnomAD v3.1.2 is 0.003621 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). At least one patient with this variant displayed an increased C14:1 level, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Supporting, PMID:24503138), from whom a pathogenic variant was also identified with unknown phase (PM3 point 0.5, PM3_Supporting, PMID:24503138). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID:32778825). The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, PP4_Supporting, PM3_Supporting, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA312255/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:7B:1

Conservation

PhyloP100: 8.38

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

PM3

PP3

PP4

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.818G>C	p.Gly273Ala	missense_variant	9/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.818G>C	p.Gly273Ala	missense_variant	9/20	1	NM_000018.4	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.000957

GnomAD3 exomes

AF:

0.000274

AC:

AN:

251436

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.000135

AC:

198

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00430

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152254

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00361

Gnomad4 AMR

AF:

0.00124

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:

0.000947

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.00158

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Uncertain:5Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 26, 2023	The NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala) in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 273 (p. Gly273Ala). The highest population minor allele frequency in gnomAD v3.1.2 is 0.003621 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (>=0.0035) for BS1, and therefore meets this criterion (BS1). At least one patient with this variant displayed an increased C14:1 level, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Supporting, PMID: 24503138), from whom a pathogenic variant was also identified with unknown phase (PM3 point 0.5, PM3_Supporting, PMID: 24503138). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 32778825). The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, PP4_Supporting, PM3_Supporting, PP3) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, 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.818G>C (NP_000009.1:p.Gly273Ala) [GRCH38: NC_000017.11:g.7222242G>C] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	The ACADVL c.818G>C; p.Gly273Ala variant (rs150149784) is reported in the literature in an individual affected with very-long chain acyl-CoA dehydrogenase deficiency who carries two other ACADVL variants, one of which is known to be pathogenic (Merritt 2014). This variant is also reported in the heterozygous state in an individual in a large inborn errors of metabolism cohort (Adhikari 2020), and is reported in ClinVar (Variation ID: 203574). This variant is found in the African/African-American population with an allele frequency of 0.34% (86/24964 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.933). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Adhikari AN et al. The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020 Sep;26(9):1392-1397. PMID: 32778825. Merritt JL 2nd et al. Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab. 2014 Apr;111(4):484-92. PMID: 24503138. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 16, 2023

Variant summary: ACADVL c.818G>C (p.Gly273Ala) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 0.00027 in 251436 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) phenotype (0.0029), suggesting that the variant may be a benign polymorphism found primarily in populations of African or African-American origin. c.818G>C has been reported in the literature as a VUS in individuals identified as positive for VLCADD by newborn screening programs in the United States, where it has mostly been reported as an uninformative genotype (i.e. zygosity not specified) and in an individual who harbored two additional variants (one pathogenic) but where phase was unspecified/unknown (e.g. Merritt_2014, Miller_2015, Adhikari_2020). These reports do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 24503138, 26385305). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503138) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.8

D;.;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.86

MVP

0.99

MPC

0.79

ClinPred

0.12

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.73

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