rs147366714

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000018.4(ACADVL):​c.947G>A​(p.Arg316Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:6

Conservation

PhyloP100: 0.0680
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-7222735-G-A is Pathogenic according to our data. Variant chr17-7222735-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203577.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADVLNM_000018.4 linkc.947G>A p.Arg316Gln missense_variant Exon 10 of 20 ENST00000356839.10 NP_000009.1 P49748-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkc.947G>A p.Arg316Gln missense_variant Exon 10 of 20 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251240
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135830
show subpopulations
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000520
AC:
76
AN:
1461836
Hom.:
0
Cov.:
32
AF XY:
0.0000413
AC XY:
30
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000594
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000464
Hom.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:5
Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 316 of the ACADVL protein (p.Arg316Gln). This variant is present in population databases (rs147366714, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency (internal data). 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: 203577). 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 not expected to disrupt ACADVL protein function with a negative 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: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NM_000018.3:c.947G>A (NP_000009.1:p.Arg316Gln) [GRCH38: NC_000017.11:g.7222735G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant dose not meet any evidence codes reported in the ACMG guidelines. -

Nov 02, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ACADVL c.947G>A; p.Arg316Gln variant (rs147366714) is not reported in the medical literature but is reported in ClinVar (Variation ID: 203577). This variant is found in the non-Finnish European population with an allele frequency of 0.005% (6/129026 alleles), in the Genome Aggregation Database. The arginine at codon 316 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.359). Due to limited information, the clinical significance of the p.Arg316Gln variant is uncertain at this time. -

May 16, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 11, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. The following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (Exon 10). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v3 <0.01 for a recessive condition (9 Heterozygotes, 0 Homozygotes). (P) 0309 - Alternative amino acid change at the same position has been observed in gnomAD (6 heterozygotes, 0 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif. The variant is in the Acyl-CoA dehydrogenase, middle domain (Protein Data Bank). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant is in the population at low frequency and has previously been described as variant of uncertain significance in multiple independent cases with consistent phenotype (ClinVar and PMID: 26385305) (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Mar 29, 2024
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Jul 21, 2016
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The R316Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R316Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.047
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.72
.;D;.
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.86
FATHMM_MKL
Benign
0.32
N
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Uncertain
0.55
D
MutationAssessor
Benign
1.1
.;L;.
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-1.5
N;.;N
REVEL
Uncertain
0.36
Sift
Benign
0.040
D;.;D
Sift4G
Benign
0.061
T;T;T
Polyphen
0.072, 0.037
.;B;B
Vest4
0.27
MVP
0.85
MPC
0.23
ClinPred
0.063
T
GERP RS
-2.0
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.1
Varity_R
0.15
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.57
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.57
Position offset: 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.

Other links and lift over

dbSNP: rs147366714; hg19: chr17-7126054; API