chr17-7223208-C-T

Variant names:

• chr17-7223208-C-T
• rs745832866
• NM_000018.4:c.1153C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP3_Moderate PP5

The NM_000018.4(ACADVL):​c.1153C>T​(p.Arg385Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,894 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R385Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:3
• Conservation: PhyloP100: 1.88
• Publications: 2 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]

MIR324 (HGNC:31767): (microRNA 324) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000018.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7223209-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 841542.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 17-7223208-C-T is Pathogenic according to our data. Variant chr17-7223208-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193786.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=5, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1153C>T	p.Arg385Trp	missense_variant	Exon 11 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1153C>T	p.Arg385Trp	missense_variant	Exon 11 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.0000398 AC: 10 AN: 251484 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461690 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727152

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44724

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74360

African (AFR) AF: 0.0000965 AC: 4 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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: 2094

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:8 Uncertain:1

Jul 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1153C>T; p.Arg385Trp variant (rs745832866; ClinVar ID: 193786), also reported as Arg345Trp, has been described in multiple individuals in association with very long-chain acyl-CoA dehydrogenase deficiency, often in trans to a second pathogenic variant (Boneh 2006, Chen 2020, Merinero 2018, Musumeci 2020, Ohashi 2004, Yamamoto 2015). The p.Arg385Trp variant is observed at a low overall frequency of 0.004% (10/251484 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.909). Consistent with predictions, functional analyses of the variant protein demonstrate a reduction in enzymatic activity compared to wildtype protein (Ohashi 2004, Chen 2020). Based on available information, this variant is considered pathogenic. REFERENCES Boneh A et al. VLCAD deficiency: pitfalls in newborn screening and confirmation of diagnosis by mutation analysis. Mol. Genet. Metab. 2006; 88(2): 166-170. PMID: 1648817. Chen T et al. Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency. J Zhejiang Univ Sci B. 2020 Nov.;21(11):885-896. PMID: 33150772. Merinero B et al. Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. JIMD Rep. 2018;39:63-74. PMID: 28755359. Musumeci O et al. A Family With a Complex Phenotype Caused by Two Different Rare Metabolic Disorders: GLUT1 and Very-Long-Chain Fatty Acid Dehydrogenase (VLCAD) Deficiencies. Front Neurol. 2020 Jun 23;11:514. PMID: 32655480. Ohashi et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004; 62(12): 2209-2213. PMID: 15210884. Yamamoto H et al. Successful management of pregnancy with very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Obstet Gynaecol Res. 2015 Jul;41(7):1126-8. PMID: 25655073. -

Jan 24, 2025

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 tryptophan, which is neutral and slightly polar, at codon 385 of the ACADVL protein (p.Arg385Trp). This variant is present in population databases (rs745832866, gnomAD 0.02%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23798014, 25655073, 28755359, 32655480). This variant is also known as R345W. ClinVar contains an entry for this variant (Variation ID: 193786). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 15210884). For these reasons, this variant has been classified as Pathogenic. -

Dec 06, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADVL c.1153C>T (p.Arg385Trp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) 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 4e-05 in 251484 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (4e-05 vs 0.0029), allowing no conclusion about variant significance. c.1153C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example Ohashi_2004, Merinero_2018, Musumeci_2020, Chen_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Ohashi_2004, Chen_2020). The most pronounced variant effect results in a reduction in enzyme activity compared to wild type. Consistently, another recent study utilized this variant as a positive control to demonstrate a barely detectable level of fatty acid oxidation (FAO) activity as determined by overexpression of the recombinant HAtagged mutant proteins in HEK293T cell lines (Chen_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic/pathogenic, n=4; VUS, n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000018.3:c.1153C>T (NP_000009.1:p.Arg385Trp) [GRCH38: NC_000017.11:g.7223208C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 15210884. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.1156C>T (p.Arg385Trp) is a missense variant that has been reported in at least five studies and found in at least five individuals with VLCAD deficiency, including a sibling pair, in a compound heterozygous state with a unique missense variant in each case (Boneh et al. 2006; Wasibren et al. 2013; Yamamoto et al. 2015; Evans et al. 2016; Merinero et al. 2017). This variant was inherited from the unaffected mother in a heterozygous state (Merinero et al. 2017) and is reported at a frequency of 0.000208 in the Latino population of the Genome Aggregation Database. Based on the collective evidence, the p.Arg386Cys 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. -

Aug 18, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:2

Apr 23, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in the presence of a second ACADVL variant in two individuals with abnormal newborn screen results who were not reported to be affected (Boneh et al., 2006; Merinero et al., 2017); Reported in the presence of a second ACADVL variant in an individual with mild intellectual disability and sporadic choreo-athetoid movements, who also complained of recurrent episodes of rhabdomyolysis triggered by exercise. A second molecular diagnosis was established that partially explained his phenotype (Musumeci et al., 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: 15210884, 32655480, 23798014, 26385305, 25655073, 27246109, 16488171, 28755359) -

ACADVL-related disorder Pathogenic:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADVL c.1153C>T variant is predicted to result in the amino acid substitution p.Arg385Trp. This variant has been reported in the compound heterozygous or homozygous states in individuals with very long chain acyl-CoA dehydrogenase deficiency (see, for example, Ohashi et al. 2004. PubMed ID: 15210884; Merinero et al. 2017. PubMed ID: 28755359; Chen et al. 2020. PubMed ID: 33150772). In vitro experimental studies suggest this variant impacts protein function (Ohashi et al. 2004. PubMed ID: 15210884; Chen et al. 2020. PubMed ID: 33150772). This variant is reported in 0.020% of alleles in individuals of Latino descent in a large population database. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;L;.
PhyloP100		1.9
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.5	D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.73
MVP		1.0
MPC		0.76
ClinPred		0.58	D
GERP RS		4.6
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.82
gMVP		0.92
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs745832866; hg19: chr17-7126527;