rs727503791

Positions:

• chr17-7221598-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_Moderate PP3 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.538G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 180 (p.Ala180Thr). This variant has been reported in patients affected with very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and elevated C14:1 and reduced VLCAD activity measured in patient lymphocytes (PP4_Moderate, PMID:26385305, 31844625, 32778825, 30194637). At least one individual was compound heterozygote with a second ACADVL variant, at least one of these variants is confirmed in trans and approved by the ACADVL VCEP as likely pathogenic (PM3, 1 point, PMID:31844625, 30194637). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino 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 0.92, 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, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 14, 2022 and the recurated classification was approved by the expert panel on April 23, 2023. LINK:https://erepo.genome.network/evrepo/ui/classification/CA295584/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:3
• Conservation: PhyloP100: 8.86

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.538G>A	p.Ala180Thr	missense_variant	7/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.538G>A	p.Ala180Thr	missense_variant	7/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251462 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461808 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 180 of the ACADVL protein (p.Ala180Thr). This variant is present in population databases (rs727503791, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency and/or very long-chain acyl-CoA dehydrogenase deficiency and a positive newborn screening result for ACADVL-related disease (PMID: 26385305, 30194637, 32798077; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166641). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2022	Variant summary: ACADVL c.538G>A (p.Ala180Thr) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) 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 1.2e-05 in 251462 control chromosomes (gnomAD). c.538G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Miller_2015, Janzen_2017, Hesse_2018). These data do not allow any conclusion about variant significance. Analysis of lymphocytes from a compound heterozygous patient with 2 missense variants, including the variant of interest, showed approximately 3% residual activity, indicating both variants were loss-of-function (Hesse_2018). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2024	- -
Likely 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.538G>A (NP_000009.1:p.Ala180Thr) [GRCH38: NC_000017.11:g.7221598G>A] 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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 02, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 13, 2018	The ACADVL c.538G>A; p.Ala180Thr variant (rs727503791) is reported in the literature to be significantly enriched in patients with abnormal newborn screening results suggestive of VLCAD deficiency (Miller 2015). This variant is reported in ClinVar (Variation ID: 166641), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at residue 180 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ala180Thr variant is considered to be likely pathogenic. References: Miller M 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; 116(3):139-45. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Apr 23, 2024	The c.538G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 180 (p.Ala180Thr). This variant has been reported in patients affected with very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and elevated C14:1 and reduced VLCAD activity measured in patient lymphocytes (PP4_Moderate, PMID: 26385305, 31844625, 32778825, 30194637). At least one individual was compound heterozygote with a second ACADVL variant, at least one of these variants is confirmed in trans and approved by the ACADVL VCEP as likely pathogenic (PM3, 1 point, PMID: 31844625, 30194637). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino 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 0.92, 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, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 14, 2022 and the recurated classification was approved by the expert panel on April 23, 2023. -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 32798077, 26385305, 29268767, 30194637, 32778825) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D;.;.;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;D;.;D;.
Vest4		0.97
MutPred		0.66		.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;
MVP		0.97
MPC		0.75
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.96
gMVP		0.81

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

Other links and lift over

dbSNP: rs727503791; hg19: chr17-7124917;