rs118204018

Variant names:

• chr17-7223707-G-A
• rs118204018
• NM_000018.4:c.1246G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7223707-G-A
• chr17-7223707-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000018.4(ACADVL):​c.1246G>A​(p.Ala416Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A416S) has been classified as Likely pathogenic.

• 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:8
• Conservation: PhyloP100: 8.82
• Publications: 10 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000018.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7223707-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 553497.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-7223707-G-A is Pathogenic according to our data. Variant chr17-7223707-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1633.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1246G>A	p.Ala416Thr	missense_variant	Exon 12 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1246G>A	p.Ala416Thr	missense_variant	Exon 12 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 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: 0.000193

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

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251462 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000219 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:8

Nov 22, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1246G>A (p.Ala416Thr) variant has been reported in at least four patients in a compound heterozygous state, two of whom had mild manifestation of VLCAD deficiency (Fukao et al. 2001; Takusa et al. 2002; Brown et al. 2014; Hesse et al. 2018). The p.Ala416Thr variant was absent from 100 controls and is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies used transient expression of the p.Ala416Thr variant and showed residual acyl-CoA dehydrogenase activity of 10-20% of wild type (Fukao et al. 2001). Based on the evidence, the ACADVL p.Ala416Thr variant is classified as likely pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 416 of the ACADVL protein (p.Ala416Thr). This variant is present in population databases (rs118204018, gnomAD 0.006%). This missense change has been observed in individual(s) with myopathic form of very-long chain acyl-CoA dehydrogenase deficiency (PMID: 11158518, 11914034, 15210884). 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: 1633). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 11158518). For these reasons, this variant has been classified as Pathogenic. -

Nov 18, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000018.3(ACADVL):c.1246G>A(A416T) is a missense variant classified as likely pathogenic in the context of very long chain acyl-CoA dehydrogenase deficiency. A416T has been observed in cases with relevant disease (PMID: 15210884, 11158518, 11914034, Mitsui_2014_(no PMID; article), 30194637). Functional assessments of this variant are available in the literature (PMID: 11158518, 20060901, 21378393). A416T has been observed in population frequency databases (gnomAD: EAS 0.01%). In summary, NM_000018.3(ACADVL):c.1246G>A(A416T) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Nov 12, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 05, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1246G>A (p.Ala416Thr) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 416. This variant has been reported in several individuals affected with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, with at least one individual showing VLCAD enzyme activity <20% of normal, which is highly specific for VLCAD deficiency (PP4_Moderate; PMID: 15210884, 20060901, 11914034, 30194637). Additionally, this variant has been reported confirmed in trans to a likely pathogenic variant and presumed in trans to several distinct variants, at least one of which is pathogenic (PM3; PMIDs: 15210884, 20060901, 11914034, 30194637). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001591 in the total population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Functional assays of fibroblasts transfected with this variant showed reduced ACADVL enzyme function indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 11158518, 11914034). The computational predictor REVEL gives a score of 0.936, 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, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). -

Feb 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M;.
PhyloP100		8.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.97, 0.95	.;D;P
Vest4		0.97
MutPred		0.91		.;Gain of methylation at K419 (P = 0.1424);.;
MVP		0.97
MPC		0.35
ClinPred		0.91	D
GERP RS		5.8
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.87
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs118204018; hg19: chr17-7127026;