17-7222789-T-G

Variant names:

• chr17-7222789-T-G
• rs398123079
• NM_000018.4:c.1001T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2_Supporting PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.1001T>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of methionine by arginine at amino acid 334 (p.Met334Arg). At least one patient with this variant displayed abnormal newborn screen and follow-up acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, which is highly specific for VLCAD (PP4_supporting, PMID:27209629) Additionally, at least six individuals with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID:26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003874 for the European (Non-Finnish) 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 0.945, 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 a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA285287/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:8
• Conservation: PhyloP100: 6.67
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• very long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: 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 rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1001T>G	p.Met334Arg	missense_variant	Exon 10 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1001T>G	p.Met334Arg	missense_variant	Exon 10 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251308 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461764 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000360 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:8

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3 Uncertain:4

Dec 22, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 15, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1001T>G; p.Met334Arg variant (rs148584617) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase deficiency (Miller 2015, Pena 2016). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 92270), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The methionine at codon 334 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). However, given the lack of clinical and functional data, the significance of the p.Met334Arg variant is uncertain at this time. References: Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PMID: 27209629.

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 334 of the ACADVL protein (p.Met334Arg). This variant is present in population databases (rs398123079, gnomAD 0.004%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 27209629; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92270). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Nov 01, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000018.3:c.1001T>G (NP_000009.1:p.Met334Arg) [GRCH38: NC_000017.11:g.7222789T>G] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM1, PP3

Oct 27, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000018.3(ACADVL):c.1001T>G(M334R) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. M334R has been observed in cases with relevant disease (PMID: 27209629). Functional assessments of this variant are not available in the literature. M334R has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1001T>G(M334R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Feb 26, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 13, 2024

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1001T>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of methionine by arginine at amino acid 334 (p.Met334Arg). At least one patient with this variant displayed abnormal newborn screen and follow-up acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, which is highly specific for VLCAD (PP4_supporting, PMID: 27209629) Additionally, at least six individuals with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003874 for the European (Non-Finnish) 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 0.945, 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 a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021)

not provided Uncertain:3

Apr 13, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple individuals with an abnormal newborn screening result for VLCAD deficiency in whom a second ACADVL variant was not identified (PMID: 26385305); Observed with a second variant in ACADVL in an asymptomatic individual diagnosed with VLCAD deficiency via molecular testing and acylcarnitine profile analysis following an abnormal newborn screening result. (PMID: 27209629); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 40149952, 27209629, 26385305)

Jul 02, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 19, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jun 04, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADVL c.1001T>G (p.Met334Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 1.6e-05 in 251308 control chromosomes (gnomAD). c.1001T>G has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency following newborn screening results (Miller_2015, Pena_2016, internal data). These data indicate that the variant may be associated with disease. 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: 26385305, 27209629). ClinVar contains an entry for this variant (Variation ID: 92270). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	.;M;.
PhyloP100		6.7
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.7	D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.88
ClinPred		0.98	D
GERP RS		4.0
PromoterAI		-0.0085	Neutral
Varity_R		0.97
gMVP		0.97
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398123079; hg19: chr17-7126108;